Testing peoples blood, including those who are pregnant, who do not have symptoms for HSV is not recommended. This is due to concerns of greater harm than benefit such as relationship problems in the setting of a high rate of tests that may be falsely positive.

Primary orofacial herpes is readily identified by clinical examination of persons with no previous history of lesions and contact with an individual with known HSV-1 infection. The appearance and distribution of sores in these individuals typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis. Adults with atypical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis. When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer) also resemble intraoral herpes, but do not present a vesicular stage.

Genital herpes can be more difficult to diagnose than oral herpes, since most HSV-2-infected persons have no classical symptoms. Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection, lichen planus, atopic dermatitis, and urethritis. Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, and polymerase chain reaction to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.

Until the 1980s serological tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice. The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection. However, a glycoprotein G-specific (IgG) HSV test introduced in the 1980s is more than 98% specific at discriminating HSV-1 from HSV-2.

It should not be confused with conditions caused by other viruses in the "herpesviridae" family such as herpes zoster, which is caused by varicella zoster virus. The differential diagnosis includes hand, foot and mouth disease due to similar lesions on the skin.

Genital herpes can be spread by viral shedding prior to and following the visual signs of symptoms.

As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men. On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is about 8–11%.

This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is around 4–5% annually. Suppressive antiviral therapy reduces these risks by 50%. Antivirals also help prevent the development of symptomatic HSV in infection scenarios, meaning the infected partner will be seropositive but symptom-free by about 50%. Condom use also reduces the transmission risk significantly. Condom use is much more effective at preventing male-to-female transmission than "vice versa". Previous HSV-1 infection may reduce the risk for acquisition of HSV-2 infection among women by a factor of three, although the one study that states this has a small sample size of 14 transmissions out of 214 couples.

However, asymptomatic carriers of the HSV-2 virus are still contagious. In many infections, the first symptom people will have of their own infections is the horizontal transmission to a sexual partner or the vertical transmission of neonatal herpes to a newborn at term. Since most asymptomatic individuals are unaware of their infection, they are considered at high risk for spreading HSV.

In October 2011, the anti-HIV drug tenofovir, when used topically in a microbicidal vaginal gel, was reported to reduce herpes virus sexual transmission by 51%.

Although it is possible to test for HPV DNA in other kinds of infections, there are no FDA-approved tests for general screening in the United States or tests approved by the Canadian government, since the testing is inconclusive and considered medically unnecessary.

Genital warts are the only visible sign of low-risk genital HPV and can be identified with a visual check. These visible growths, however, are the result of non-carcinogenic HPV types. Five percent acetic acid (vinegar) is used to identify both warts and squamous intraepithelial neoplasia (SIL) lesions with limited success by causing abnormal tissue to appear white, but most doctors have found this technique helpful only in moist areas, such as the female genital tract. At this time, HPV test for males are used only in research.

Research into testing for HPV by antibody presence has been done. The approach is looking for an immune response in blood, which would contain antibodies for HPV if the patient is HPV positive. The reliability of such tests hasn't been proven, as there hasn't been a FDA approved product as of March 2014; testing by blood would be a less invasive test for screening purposes.

The diagnosis of genital warts is most often made visually, but may require confirmation by biopsy in some cases. Smaller warts may occasionally be confused with molluscum contagiosum.

Genital warts, histopathologically, characteristically rise above the skin surface due to enlargement of the dermal papillae, have parakeratosis and the characteristic nuclear changes typical of HPV infections (nuclear enlargement with perinuclear clearing).

DNA tests are available for diagnosis of high-risk HPV infections. Because genital warts are caused by low-risk HPV types, DNA tests cannot be used for diagnosis of genital warts or other low-risk HPV infections.

Some practitioners use an acetic acid solution to identify smaller warts ("subclinical lesions"), but this practice is controversial. Because a diagnosis made with acetic acid will not meaningfully affect the course of the disease, and cannot be verified by a more specific test, a 2007 UK guideline advises against its use.

Research studies have tested for and found HPV, including high-risk types (i.e. the types found in cancers), on fingers, mouth, saliva, anus, urethra, urine, semen, blood, scrotum and penis. However, most research tests have used Dacron swabs and custom analysis not available to the general public.

A Brazilian study used the readily available Qiagen/Digene test mentioned above (off label) to test men's penis, scrotum and anus. Each of the 50 men had been a partner for at least 6 months of a woman who was positive for high-risk HPV. They found high-risk HPV on 60% of these men, primarily the penis. "The specimens were obtained using a vigorous motion of the conical brush included in the Digene kit after spraying the anogenital region with saline solution."

A slightly different method also used cytobrushes (but custom lab analysis) and found 37% of 582 Mexican army recruits positive for high risk HPV. They were told not to wash genitals for 12 hours before sampling. (Other studies are silent on washing, a particular gap in studies of hands). They included the urethra as well as scrotum and penis, but the urethra added less than 1% to the HPV rate. Studies like this led Giuliano to recommend sampling the glans, shaft and crease between them and scrotum, since sampling the urethra or anus added very little to diagnosis. Dunne recommends glans, shaft, their crease, and foreskin.

A small study of cytobrushes on 10 US men where the brush was wet, rather than the skin, found 2 of 10 men were positive for HPV (type not reported). Their lab analysis was not the same as either study above. This small study found 4 of 10 men positive for HPV when the skin was rubbed with 600 grit emery paper, then swabbed with a wet Dacron swab. Since emery paper and brush were analyzed together at the lab, it is not known if the emery paper collected viruses or loosened them for the swab to collect.

Studies have found collection by men from their own skin (with emery paper and Dacron swabs) as effective as by a clinician, sometimes more so, since patients were more willing to scrape vigorously.

Other studies have used similar cytobrushes to sample fingertips and under the fingernails, though without wetting the area or brush.

Other studies analyzed urine, semen, and blood and found varying amounts of HPV, but there is no publicly available test for them.

There is not a wide range of tests even though HPV is common. Clinicians depend on the vaccine among young people and high clearance rates (see Clearance subsection in Virology) to create a low risk of disease and mortality, and treat the cancers when they appear. Others believe that reducing HPV infection in more men and women, even when it has no symptoms, is important (herd immunity) to prevent more cancers rather than just treating them. Where tests are used, negative test results show safety from transmission, and positive test results show where shielding (condoms, gloves) is needed to prevent transmission until the infection clears.

Shingles can be confused with herpes simplex, dermatitis herpetiformis and impetigo, and skin reactions caused by contact dermatitis, candidiasis, certain drugs and insect bites.

Specific age groups, persons who participate in risky sexual behavior, or those have certain health conditions may require screening. The CDC recommends that sexually active women under the age of 25 and those over 25 at risk should be screened for chlamydia and gonorrhea yearly. Appropriate times for screening are during regular pelvic examinations and preconception evaluations. Nucleic acid amplification tests are the recommended method of diagnosis for gonorrhea and chlamydia. This can be done on either urine in both men and women, vaginal or cervical swabs in women, or urethral swabs in men. Screening can be performed:

- to assess the presence of infection and prevent tubal infertility in women

- during the initial evaluation before infertility treatment

- to identify HIV infection

- for men who have sex with men

- for those who may have been exposed to hepatitis C

- for HCV

The majority of cases (85%) occur during birth when the baby comes in contact with infected genital secretions in the birth canal, most common with mothers that have newly been exposed to the virus (mothers that had the virus before pregnancy have a lower risk of transmission), an estimated 5% are infected in utero, and approximately 10% of cases are acquired postnatally. Detection and prevention is difficult because transmission is asymptomatic in 60% - 98% of cases.

Gardasil (sold by Merck & Co.) is a vaccine that protects against human papillomavirus types 6, 11, 16 and 18. Types 6 and 11 cause genital warts, while 16 and 18 cause cervical cancer. The vaccine is preventive, not therapeutic, and must be given before exposure to the virus type to be effective, ideally before the beginning of sexual activity. The vaccine is approved by the US Food and Drug Administration for use in both males and females as early as 9 years of age.

In the UK, Gardasil replaced Cervarix in September 2012 for reasons unrelated to safety. Cervarix had been used routinely in young females from its introduction in 2008, but was only effective against the high-risk HPV types 16 and 18, neither of which typically causes warts.

From bubo pus or ulcer secretions, "H. ducreyi" can be identified. PCR-based identification of organisms is available. Simple, rapid, sensitive and inexpensive antigen detection methods for "H. ducreyi" identification are also popular. Serologic detection of "H. ducreyi" is and uses outer membrane protein and lipooligosaccharide.

Reductions in morbidity and mortality are due to the use of antiviral treatments such as vidarabine and acyclovir. However, morbidity and mortality still remain high due to diagnosis of DIS and CNS herpes coming too late for effective antiviral administration; early diagnosis is difficult in the 20-40% of infected neonates that have no visible lesions. A recent large scale retrospective study found disseminated NHSV patients least likely to get timely treatment, contributing to the high morbidity/mortality in that group.

Harrison's Principles of Internal Medicine, recommends that pregnant women with active genital herpes lesions at the time of labor be delivered by caesarean section. Women whose herpes is not active can be managed with acyclovir. The current practice is to deliver women with primary or first episode non primary infection via caesarean section, and those with recurrent infection vaginally, even in the presence of lesions because of the low risk (1-3%) of vertical transmission associated with recurrent herpes.

Despite many distinguishing features, the clinical spectrums of following diseases may overlap with chancroid:

- Primary syphilis

- Genital herpes

Practical clinical approach for this STI as Genital Ulcer Disease is to rule out top differential diagnosis of Syphilis and Herpes and consider empirical treatment for Chancroid as testing is not commonly done for the latter.

Key measures to prevent outbreaks of the disease are maintaining hygiene standards and using screening to exclude persons with suspicious infections from engaging in contact sports. A skin check performed before practice or competition takes place can identify individuals who should be evaluated, and if necessary treated by a healthcare professional. In certain situations, i.e. participating in wrestling camps, consider placing participants on valacyclovir 1GM daily for the duration of camp. 10-year study has shown 89.5% reduction in outbreaks and probable prevention of contracting the virus. Medication must be started 5 days before participation to ensure proper concentrations exist.

If the rash has appeared, identifying this disease (making a differential diagnosis) requires only a visual examination, since very few diseases produce a rash in a dermatomal pattern (see map). However, herpes simplex virus (HSV) can occasionally produce a rash in such a pattern (zosteriform herpes simplex). The Tzanck smear is helpful for diagnosing acute infection with a herpes virus, but does not distinguish between HSV and VZV.

When the rash is absent (early or late in the disease, or in the case of zoster sine herpete), shingles can be difficult to diagnose. Apart from the rash, most symptoms can occur also in other conditions.

Laboratory tests are available to diagnose shingles. The most popular test detects VZV-specific IgM antibody in blood; this appears only during chickenpox or shingles and not while the virus is dormant. In larger laboratories, lymph collected from a blister is tested by polymerase chain reaction for VZV DNA, or examined with an electron microscope for virus particles. Molecular biology tests based on in vitro nucleic acid amplification (PCR tests) are currently considered the most reliable. Nested PCR test has high sensitivity, but is susceptible to contamination leading to false positive results. The latest real-time PCR tests are rapid, easy to perform, and as sensitive as nested PCR, and have a lower risk of contamination. They also have more sensitivity than viral cultures.

Testing may be for a single infection, or consist of a number of tests for a range of STIs, including tests for syphilis, trichomonas, gonorrhea, chlamydia, herpes, hepatitis and HIV. No procedure tests for all infectious agents.

STI tests may be used for a number of reasons:

- as a diagnostic test to determine the cause of symptoms or illness

- as a screening test to detect asymptomatic or presymptomatic infections

- as a check that prospective sexual partners are free of disease before they engage in sex without safer sex precautions (for example, when starting a long term mutually monogamous sexual relationship, in fluid bonding, or for procreation).

- as a check prior to or during pregnancy, to prevent harm to the baby

- as a check after birth, to check that the baby has not caught an STI from the mother

- to prevent the use of infected donated blood or organs

- as part of the process of contact tracing from a known infected individual

- as part of mass epidemiological surveillance

Early identification and treatment results in less chance to spread disease, and for some conditions may improve the outcomes of treatment. There is often a window period after initial infection during which an STI test will be negative. During this period, the infection may be transmissible. The duration of this period varies depending on the infection and the test. Diagnosis may also be delayed by reluctance of the infected person to seek a medical professional. One report indicated that people turn to the Internet rather than to a medical professional for information on STIs to a higher degree than for other sexual problems.

The likelihood of the infection being spread can be reduced through behaviors such as avoiding touching an active outbreak site, washing hands frequently while the outbreak is occurring, not sharing items that come in contact with the mouth, and not coming into close contact with others (by avoiding kissing, oral sex, or contact sports).

Because the onset of an infection is difficult to predict, lasts a short period of time and heals rapidly, it is difficult to conduct research on cold sores. Though famciclovir improves lesion healing time, it is not effective in preventing lesions; valaciclovir and a mixture of acyclovir and hydrocortisone are similarly useful in treating outbreaks but may also help prevent them.

Acyclovir and valacyclovir by mouth are effective in preventing recurrent herpes labialis if taken prior to the onset of any symptoms or exposure to any triggers. Evidence does not support L-lysine.

Herpes simplex virus is commonly found in humans, yet uncommonly results in systemic manifestations. Suppression of HIV with antiretroviral medications, careful monitoring of immunosuppressive medications are important means of prevention. Antiviral prophylaxis such as daily acyclovir in immunocompromised individuals may be considered.

CMV, VZV as well as HIV infections of the esophagus can have a similar presentation. Tissue culture is the most accurate means of distinguishing between the different viral causes. Caustic esophagitis, pill-induced esophagitis as well as yeast esophagitis can have a similar clinical presentation.

Although it is a self-limited illness, oral or intravenous antiviral treatments, particularly acyclovir, have been used in the management of immunocompromised or severely infected patients. Topical acyclovir has not been shown to be effective in management of herpetic whitlow. Famciclovir has been demonstrated to effectively treat and prevent recurrent episodes. Lancing or surgically debriding the lesion may make it worse by causing a superinfection or encephalitis.

Herpes outbreaks should be treated with antiviral medications like Acyclovir, Valacyclovir, or Famcyclovir, each of which is available in tablet form.

Oral antiviral medication is often used as a prophylactic to suppress or prevent outbreaks from occurring. The recommended dosage for suppression therapy for recurrent outbreaks is 1,000 mg of valacyclovir once a day or 400 mg Acyclovir taken twice a day. In addition to preventing outbreaks, these medications greatly reduce the chance of infecting someone while the patient is not having an outbreak.

Often, people have regular outbreaks of anywhere from 1 to 10 times per year, but stress (because the virus lies next to the nerve cells), or a weakened immune system due to a temporary or permanent illness can also spark outbreaks. Some people become infected but fail to ever have a single outbreak, although they remain carriers of the virus and can pass the disease on to an uninfected person through asymptomatic shedding (when the virus is active on the skin but rashes or blisters do not appear).

The use of antiviral medications has been shown to be effective in preventing acquisition of the herpes virus. Specific usage of these agents focus on wrestling camps where intense contact between individuals occur on a daily basis over several weeks. They have also been used for large outbreaks during seasonal competition, but further research needs to be performed to verify efficacy.

Docosanol, a saturated fatty alcohol, is a safe and effective topical application that has been approved by the United States Food and Drug Administration for herpes labialis in adults with properly functioning immune systems. It is comparable in effectiveness to prescription topical antiviral agents. Due to its mechanism of action, there is little risk of drug resistance. The duration of symptoms can be shortened a bit if an antiviral, anesthetic, zinc oxide or zinc sulfate cream is applied soon after it starts.

Effective antiviral medications include acyclovir and penciclovir, which can speed healing by as much as 10%. Famciclovir or valacyclovir, taken in pill form, can be effective using a single day, high-dose application and is more cost effective and convenient than the traditional treatment of lower doses for 5–7 days.

In children the primary source of infection is the orofacial area, and it is commonly inferred that the virus (in this case commonly HSV-1) is transferred by the cutting, chewing or sucking of fingernail or thumbnail.

In adults, it is more common for the primary source to be the genital region, with a corresponding preponderance of HSV-2. It is also seen in adult health care workers such as dentists because of increased exposure to the herpes virus.

Contact sports are also a potential source of infection with herpetic whitlows.

When physical examination of the newborn shows signs of a vertically transmitted infection, the examiner may test blood, urine, and spinal fluid for evidence of the infections listed above. Diagnosis can be confirmed by culture of one of the specific pathogens or by increased levels of IgM against the pathogen.