Abnormal laboratory findings seen in patients with Rocky Mountain spotted fever may include a low platelet count, low blood sodium concentration, or elevated liver enzyme levels. Serology testing and skin biopsy are considered to be the best methods of diagnosis. Although immunofluorescent antibody assays are considered some of the best serology tests available, most antibodies that fight against "R. rickettsii" are undetectable on serology tests the first seven days after infection.

Differential diagnosis includes dengue, leptospirosis, and, most recently, chikungunya and Zika virus infections.

Biopsies or cultures of a person's tick wound (eschar) are used to diagnose ATBF. However, this requires special culture media and can only be done by a laboratory with biohazard protection. There are more specialized laboratory tests available that use quantitative polymerase chain reactions (qPCR), but can only be done by laboratories with special equipment. Immunofluorescence assays can also be used, but are hard to interpret because of cross-reactions with other rickettsiae bacteria.

Diagnosis is usually based on serology (looking for an antibody response) rather than looking for the organism itself. Serology allows the detection of chronic infection by the appearance of high levels of the antibody against the virulent form of the bacterium. Molecular detection of bacterial DNA is increasingly used. Culture is technically difficult and not routinely available in most microbiology laboratories.

Q fever can cause endocarditis (infection of the heart valves) which may require transoesophageal echocardiography to diagnose. Q fever hepatitis manifests as an elevation of alanine transaminase and aspartate transaminase, but a definitive diagnosis is only possible on liver biopsy, which shows the characteristic fibrin ring granulomas.

Diagnosis of ATBF is mostly based on symptoms, as many laboratory tests are not specific for ATBF. Common laboratory test signs of ATBF are a low white blood cell count (lymphopenia) and low platelet count (thrombocytopenia), a high C-reactive protein, and mildly high liver function tests.

Serological testing is typically used to obtain a definitive diagnosis. Most serological tests would succeed only after a certain period of time past the symptom onset (usually a week). The differential diagnosis list includes typhus, ehrlichiosis, leptospirosis, Lyme disease and virus-caused exanthema (measles or rubella).

The diagnosis of relapsing fever can be made on blood smear as evidenced by the presence of spirochetes. Other spirochete illnesses (Lyme disease, syphilis, leptospirosis) do not show spirochetes on blood smear. Although considered the gold standard, this method lacks sensitivity and has been replaced by PCR in many settings.

Protection is offered by Q-Vax, a whole-cell, inactivated vaccine developed by an Australian vaccine manufacturing company, CSL Limited. The intradermal vaccination is composed of killed "C. burnetii" organisms. Skin and blood tests should be done before vaccination to identify pre-existing immunity, because vaccinating people who already have an immunity can result in a severe local reaction. After a single dose of vaccine, protective immunity lasts for many years. Revaccination is not generally required. Annual screening is typically recommended.

In 2001, Australia introduced a national Q fever vaccination program for people working in “at risk” occupations. Vaccinated or previously exposed people may have their status recorded on the Australian Q Fever Register, which may be a condition of employment in the meat processing industry. An earlier killed vaccine had been developed in the Soviet Union, but its side effects prevented its licensing abroad.

Preliminary results suggest vaccination of animals may be a method of control. Published trials proved that use of a registered phase vaccine (Coxevac) on infected farms is a tool of major interest to manage or prevent early or late abortion, repeat breeding, anoestrus, silent oestrus, metritis, and decreases in milk yield when "C. burnetii" is the major cause of these problems.

Currently, no vaccine against relapsing fever is available, but research continues. Developing a vaccine is very difficult because the spirochetes avoid the immune response of the infected person (or animal) through antigenic variation. Essentially, the pathogen stays one step ahead of antibodies by changing its surface proteins. These surface proteins, lipoproteins called variable major proteins, have only 30–70% of their amino acid sequences in common, which is sufficient to create a new antigenic "identity" for the organism. Antibodies in the blood that are binding to and clearing spirochetes expressing the old proteins do not recognize spirochetes expressing the new ones. Antigenic variation is common among pathogenic organisms. These include the agents of malaria, gonorrhea, and sleeping sickness. Important questions about antigenic variation are also relevant for such research areas as developing a vaccine against HIV and predicting the next influenza pandemic.

Yellow fever is most frequently a clinical diagnosis, made on the basis of symptoms and the diseased person's whereabouts prior to becoming ill. Mild courses of the disease can only be confirmed virologically. Since mild courses of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea and vomiting six to 10 days after leaving the affected area) is treated seriously.

If yellow fever is suspected, the virus cannot be confirmed until six to 10 days after the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma; this can take one to four weeks.

Serologically, an enzyme linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG-titer (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a fourfold increase in IgG-titer is considered sufficient indication for yellow fever. Since these tests can cross-react with other flaviviruses, like dengue virus, these indirect methods cannot conclusively prove yellow fever infection.

Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens. Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable "post mortem" to confirm the cause of death.

In a differential diagnosis, infections with yellow fever must be distinguished from other feverish illnesses like malaria. Other viral hemorrhagic fevers, such as Ebola virus, Lassa virus, Marburg virus, and Junin virus, must be excluded as cause.

The diagnosis of dengue fever may be confirmed by microbiological laboratory testing. This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection (such as for NS1) or specific antibodies (serology). Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost. Detection of NS1 during the febrile phase of a primary infection may be greater than 90% sensitive however is only 60–80% in subsequent infections. All tests may be negative in the early stages of the disease. PCR and viral antigen detection are more accurate in the first seven days. In 2012 a PCR test was introduced that can run on equipment used to diagnose influenza; this is likely to improve access to PCR-based diagnosis.

These laboratory tests are only of diagnostic value during the acute phase of the illness with the exception of serology. Tests for dengue virus-specific antibodies, types IgG and IgM, can be useful in confirming a diagnosis in the later stages of the infection. Both IgG and IgM are produced after 5–7 days. The highest levels (titres) of IgM are detected following a primary infection, but IgM is also produced in reinfection. IgM becomes undetectable 30–90 days after a primary infection, but earlier following re-infections. IgG, by contrast, remains detectable for over 60 years and, in the absence of symptoms, is a useful indicator of past infection. After a primary infection, IgG reaches peak levels in the blood after 14–21 days. In subsequent re-infections, levels peak earlier and the titres are usually higher. Both IgG and IgM provide protective immunity to the infecting serotype of the virus. In testing for IgG and IgM antibodies there may be cross-reactivity with other flaviviruses which may result in a false positive after recent infections or vaccinations with yellow fever virus or Japanese encephalitis. The detection of IgG alone is not considered diagnostic unless blood samples are collected 14 days apart and a greater than fourfold increase in levels of specific IgG is detected. In a person with symptoms, the detection of IgM is considered diagnostic.

Rocky Mountain spotted fever can be a very severe illness and patients often require hospitalization. Because "R. rickettsii" infects the cells lining blood vessels throughout the body, severe manifestations of this disease may involve the respiratory system, central nervous system, gastrointestinal system, or kidneys.

Long-term health problems following acute Rocky Mountain spotted fever infection include partial paralysis of the lower extremities, gangrene requiring amputation of fingers, toes, or arms or legs, hearing loss, loss of bowel or bladder control, movement disorders, and language disorders. These complications are most frequent in persons recovering from severe, life-threatening disease, often following lengthy hospitalizations

The illness can be treated with tetracyclines (doxycycline is the preferred treatment), chloramphenicol, macrolides or fluoroquinolones.

The diagnosis is made with serologic methods, either the classic Weil-Felix test

(agglutination of Proteus OX strains ), ELISA, or immunofluorescence assays in the bioptic material of the primary lesion.

Although commercial tests are not readily available, diagnosis can be confirmed by serology-based assays or quantitative PCR by laboratories that have developed assays to perform such identification.

The disease can be fatal if left untreated, but endemic typhus is highly treatable with antibiotics. Most people recover fully, but death may occur in the elderly, severely disabled or patients with a depressed immune system. The most effective antibiotics include tetracycline and chloramphenicol. In United States, CDC recommends solely doxycycline.

The World Health Organization's 2009 classification divides dengue fever into two groups: uncomplicated and severe. This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, though the older classification is still widely used including by the World Health Organization's Regional Office for South-East Asia as of 2011. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage while all other cases are uncomplicated. The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever. Dengue hemorrhagic fever was subdivided further into grades I–IV. Grade I is the presence only of easy bruising or a positive tourniquet test in someone with fever, grade II is the presence of spontaneous bleeding into the skin and elsewhere, grade III is the clinical evidence of shock, and grade IV is shock so severe that blood pressure and pulse cannot be detected. Grades III and IV are referred to as "dengue shock syndrome".

Tetracycline-group antibiotics (doxycycline, tetracycline) are commonly used. Chloramphenicol is an alternative medication recommended under circumstances that render use of tetracycline derivates undesirable, such as severe liver malfunction, kidney deficiency, in children under nine years and in pregnant women. The drug is administered for seven to ten days.

The treatment for bacillary angiomatosis is erythromycin given for three to four months.

The American Public Health Association recommends treatment based upon clinical findings and before culturing confirms the diagnosis. Without treatment, death may occur in 10 to 60 percent of patients with epidemic typhus, with patients over age 60 having the highest risk of death. In the antibiotic era, death is uncommon if doxycycline is given. In one study of 60 hospitalized patients with epidemic typhus, no patient died when given doxycycline or chloramphenicol. Some patients also may need oxygen and intravenous (IV) fluids.

No rapid laboratory tests are available to diagnose rickettsial diseases early in the course of illness, and serologic assays usually take 10-12 days to become positive. Research is indicating that swabs of eschars may be used for molecular detection of rickettsial infections.

Providing basic sanitation and safe drinking water and food is the key for controlling the disease. In developed countries, enteric fever rates decreased in the past when treatment of municipal water was introduced, human feces were excluded from food production, and pasteurization of dairy products began. In addition, children and adults should be carefully educated about personal hygiene. This would include careful handwashing after defecation and sexual contact, before preparing or eating food, and especially the sanitary disposal of feces. Food handlers should be educated in personal hygiene prior to handling food or utensils and equipment. Infected individuals should be advised to avoid food preparation. Sexually active people should be educated about the risks of sexual practices that permit fecal-oral contact.

Those who travel to countries with poor sanitation should receive a live attenuated typhoid vaccine—Ty21a (Vivotif), which, in addition to the protection against typhoid fever, and may provide some protection against paratyphoid fever caused by the "S. enterica" serotypes A and B. In particular, a reanalysis of data from a trial conducted in Chile showed the Ty21a vaccine was 49% effective (95% CI: 8–73%) in preventing paratyphoid fever caused by the serotype B. Evidence from a study of international travelers in Israel also indicates the vaccine may prevent a fraction of infections by the serotype A, although no trial confirms this. This cross-protection by a typhoid vaccine is most likely due to O antigens shared between different "S. enterica" serotypes.

Exclusion from work and social activities should be considered for symptomatic, and asymptomatic, people who are food handlers, healthcare/daycare staff who are involved in patient care and/or child care, children attending unsanitary daycare centers, and older children who are unable to implement good standards of personal hygiene. The exclusion applies until two consecutive stool specimens are taken from the infected patient and are reported negative.

Doxycycline has been used in the treatment of rickettsial infection.

Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. WHO now states that a single dose of vaccination is sufficient to confer lifelong immunity against yellow fever disease." The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler. The World Health Organization (WHO) recommends routine vaccinations for people living in affected areas between the 9th and 12th month after birth.

Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine–associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases.

The Yellow Fever Initiative, launched by WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI Alliance, and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected.

In March 2017, WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil.

As of 2017 there is no commercially available vaccine. A vaccine has been in development for scrub typhus known as the scrub typhus vaccine.

There is no specific treatment for the disease. Pain killers and fluid replacement may be useful.

A combination of clinical signs, symptoms, and laboratory tests can confirm the likelihood of having CTF. Some tests include complement fixation to Colorado tick virus, immunofluorescence for Colorado tick fever, and some other common laboratory findings suggestive of CTF, including leucopenia, thrombocytopenia, and mildly elevated liver enzyme levels.

Detection of viral antibodies on red blood cells is possible.