For early cases, prompt treatment is usually curative. However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, and simultaneous infection with other tick-borne diseases (coinfections), including ehrlichiosis, babesiosis, and immune suppression in the patient.

It is believed that less than 5% of people have lingering symptoms of fatigue, pain, or joint and muscle aches at the time they finish treatment. These symptoms can last for more than 6 months. This condition is called post-treatment lyme disease syndrome. As of 2016 the reason for the lingering symptoms was not known; the condition is generally managed similarly to fibromyalgia or chronic fatigue syndrome.

In dogs, a serious long-term prognosis may result in glomerular disease, which is a category of kidney damage that may cause chronic kidney disease. Dogs may also experience chronic joint disease if the disease is left untreated. However, the majority of cases of Lyme disease in dogs result in a complete recovery with, and sometimes without, treatment with antibiotics. In rare cases, Lyme disease can be fatal to both humans and dogs.

Outdoor workers are at risk of Lyme disease if they work at sites with infected ticks. In 2010, the highest number of confirmed Lyme disease cases were reported from New Jersey, Pennsylvania, Wisconsin, New York, Massachusetts, Connecticut, Minnesota, Maryland, Virginia, New Hampshire, Delaware, and Maine. U.S. workers in the northeastern and north-central States are at highest risk of exposure to infected ticks. Ticks may also transmit other tick-borne diseases to workers in these and other regions of the country. Worksites with woods, bushes, high grass, or leaf litter are likely to have more ticks. Outdoor workers should be extra careful to protect themselves in the late spring and summer when young ticks are most active.

Chronic Lyme disease is a generally unrecognised diagnosis that encompasses "a broad array of illnesses or symptom complexes for which there is no reproducible or convincing scientific evidence of any relationship to "B. burgdorferi" infection." There is no clinical evidence that "chronic" Lyme disease is caused by a persistent infection. It is distinct from post-treatment Lyme disease syndrome, a set of lingering symptoms which may persist after successful treatment of infection with Lyme spirochetes. The symptoms of "chronic Lyme" are generic and non-specific "symptoms of life".

A number of alternative treatments are promoted for "chronic Lyme disease", of which possibly the most controversial and harmful is long-term antibiotic therapy, particularly intravenous antibiotics. Most medical authorities advise against long-term antibiotic treatment for Lyme disease, though they agree that some patients do experience lingering symptoms. Following disciplinary proceedings by State medical licensing boards in the United States, a subculture of "Lyme literate" physicians has successfully lobbied for specific legal protections, exempting them from the standard of care and Infectious Diseases Society of America treatment guidelines. This "troubling" political interference in medical care has been criticised as an example of "legislative alchemy", the process whereby pseudomedicine is legislated into practice.

Infectious pathogen-associated diseases include many of the most common and costly chronic illnesses. The treatment of chronic diseases accounts for 75% of all US healthcare costs (amounting to $1.7 trillion in 2009).

The term "chronic Lyme disease" is often applied to several different sets of people. One usage refers to people suffering from the symptoms of untreated and disseminated late-stage Lyme disease: arthritis, peripheral neuropathy and/or encephalomyelitis. The term is also applied to people who have had the disease in the past and some symptoms remain after antibiotic treatment, which is also called post-Lyme disease syndrome. A third and controversial use of the term applies to patients with nonspecific symptoms, such as fatigue, who show no objective evidence they have been infected with Lyme disease in the past, since the standard diagnostic tests for infection are negative.

The Centers for Disease Control and Prevention state that some people after a "course of antibiotics will have lingering symptoms of fatigue, pain, or joint and muscle aches. In some cases, these can last for more than 6 months. Although often called 'chronic Lyme disease', this condition is properly known as 'post-treatment Lyme disease syndrome' (PTLDS)". This is estimated to occur in less than 5% of people who had Lyme disease and were treated.

While it is undisputed people can have severe symptoms, the cause and appropriate treatment are controversial. The symptoms may represent "for all intents and purposes" fibromyalgia or chronic fatigue syndrome. A few doctors attribute these symptoms to persistent infection with "Borrelia", or co-infections with other tick-borne pathogens, such as "Ehrlichia" and "Babesia". Other doctors believe that the initial infection may cause an autoimmune reaction that continues to cause serious symptoms even after the bacteria have been eliminated by antibiotics. A review looked at several animal studies that found persistence of live but disabled spirochetes following treatment of "B. burgdorferi" infection with antibiotics. The authors noted that none of the lingering spirochetes were associated with inflamed tissues and criticized the studies for not considering adequately the different pharmacodynamics and pharmacokinetics of the antibiotics used to treat the animals in the trials versus what would be expected to be used to treat humans. The authors concluded, "There is no scientific evidence to support the hypothesis that such spirochetes, should they exist in humans, are the cause of post-Lyme disease syndrome."

Major US medical authorities, including the Infectious Diseases Society of America, the American Academy of Neurology, and the National Institutes of Health, have stated there is no convincing evidence that "Borrelia" is involved in the various symptoms classed as chronic Lyme disease, and advise against long-term antibiotic treatment as ineffective and possibly harmful. Prolonged antibiotic therapy presents significant risks and can have dangerous side effects. Randomized placebo-controlled studies have shown that antibiotics offer no sustained benefit in people with "chronic Lyme"; with evidence of both placebo effects and significant adverse effects from such treatment. An advocacy group called the International Lyme And Associated Diseases Society (ILADS) argues the persistence of "B. burgdorferi" may be responsible for manifestations of late Lyme disease symptoms. It has questioned the generalizability and reliability of some of the above trials and the reliability of the current diagnostic tests.

Other causes or associations of disease are: a compromised immune system, environmental toxins, radiation exposure, diet and lifestyle choices, stress, and genetics. Diseases may also be multifactorial, requiring multiple factors to induce disease. For example: in a murine model, Crohn's disease can be precipitated by a norovirus, but only when both a specific gene variant is present and a certain toxin has damaged the gut.

No serious long-term effects are known for this disease, but preliminary evidence suggests, if such symptoms do occur, they are less severe than those associated with Lyme disease.

Infections are treated with antibiotics, particularly doxycycline, and the acute symptoms appear to respond to these drugs.

The Baggio–Yoshinari syndrome (BYS), formerly known as the Brazilian Lyme-like disease and Brazilian human borreliosis, is a disease transmitted by the "Amblyomma cajennense" tick, but the organism that causes the infection is still unknown. Clinical features resemble those of Lyme disease (LD).

Neuroborreliosis, also known as Lyme neuroborreliosis (LNB), is a disorder of the central nervous system. A neurological manifestation of Lyme disease, neuroborreliosis is caused by a systemic infection of spirochetes of the genus "Borrelia." Symptoms of the disease include erythema migrans and flu-like symptoms. The microbiological progression of the disease is similar to that of neurosyphilis, another spirochetal infection.

In 1989, Brazilian researchers Professors Domingos Baggio (an entomologist from the Biomedical Sciences Institute of the University of São Paulo), Paulo Yasuda (a microbiologist from the same institute) and Natalino Hajime Yoshinari (a physician from the Rheumatology Department at University of São Paulo's Medical School) started research on Lyme disease in Brazil, by suggestion of Dr. Allen Steere. At that time, LD was almost unknown among Brazilian physicians.

The first cases were described in Brazil in 1992 in siblings from Cotia, São Paulo that developed symptoms as a migrating redness, general flu-like symptoms and arthritis after being bitten by ticks. Although the symptoms were similar to those presented by patients of Lyme disease, clinical and laboratorial results were considerably different. Ticks of the "Ixodes ricinus" complex were not found at the risk areas; bacteria from the "Borrelia burgdorferi" sensu lato complex —that cause Lyme disease— were not found in biological fluids and tissues of the siblings. Blood analysis of the patients on electron microscopy exhibited structures resembling microorganisms of the spirochaete phylum. For these reasons, the Brazilian zoonosis was considered a new disease and named Baggio–Yoshinari Syndrome (BYS), defined as: "Exotic and emerging Brazilian infectious disease, transmitted by ticks not belonging to the "Ixodes ricinus" complex, caused by latent spirochetes with atypical morphology, which originates LD-like symptoms, except for occurrence of relapsing episodes and auto-immune disorders".

Neuroborreliosis is often preceded by the typical symptoms of Lyme disease, which include erythema migrans and flu-like symptoms such as fever and muscle aches. Neurologic symptoms of neuroborreliosis include the meningoradiculitis (which is more common in European patients), cranial nerve abnormalities, and altered mental status. Sensory findings may also be present. Rarely, a progressive form of encephalomyelitis may occur. In children, symptoms of neuroborreliosis include headache, sleep disturbance, and symptoms associated with increased intracranial pressure, such as papilledema, can occur. Less common childhood symptoms can include meningitis, myelitis, ataxia, and chorea. Ocular Lyme disease has also been reported, as has neuroborreliosis affecting the spinal cord, but neither of these findings are common.

Missouri Lyme disease is a cutaneous condition. The cause of ‘Missouri Lyme disease’ has been a source of controversy. True Lyme disease probably occurs in Missouri and other southern states, although Lyme disease-like illnesses not related to Borrelia burgdorferi also occur. Strains of B. burgdorferi have been isolated from A. americanum in Missouri, but the ticks are not efficient disease vectors.

For a person or companion animal to acquire a tick-borne disease requires that that individual gets bitten by a tick and that that tick feeds for a sufficient period of time. The feeding time required to transmit pathogens differs for different ticks and different pathogens. Transmission of the bacterium that causes Lyme disease is well understood to require a substantial feeding period.

For an individual to acquire infection, the feeding tick must also be infected. Not all ticks are infected. In most places in the US, 30-50% of deer ticks will be infected with "Borrelia burgdorferi" (the agent of Lyme disease). Other pathogens are much more rare. Ticks can be tested for infection using a highly specific and sensitive qPCR procedure. Several commercial labs provide this service to individuals for a fee. The Laboratory of Medical Zoology (LMZ), a nonprofit lab at the University of Massachusetts, provides a comprehensive TickReport for a variety of human pathogens and makes the data available to the public. Those wishing to know the incidence of tick-borne diseases in their town or state can search the LMZ surveillance database.

Ticks tend to be more active during warmer months, though this varies by geographic region and climate. Areas with woods, bushes, high grass, or leaf litter are likely to have more ticks. Those bitten commonly experience symptoms such as body aches, fever, fatigue, joint pain, or rashes. People can limit their exposure to tick bites by wearing light-colored clothing (including pants and long sleeves), using insect repellent with 20%–30% DEET, tucking their pants legs into their socks, checking for ticks frequently, and washing and drying their clothing (in a hot dryer).

The U.S. Centers for Disease Control and Prevention (CDC) publishes a journal "Emerging Infectious Diseases" that identifies the following factors contributing to disease emergence:

- Microbial adaption; e.g. genetic drift and genetic shift in Influenza A

- Changing human susceptibility; e.g. mass immunocompromisation with HIV/AIDS

- Climate and weather; e.g. diseases with zoonotic vectors such as West Nile Disease (transmitted by mosquitoes) are moving further from the tropics as the climate warms

- Change in human demographics and trade; e.g. rapid travel enabled SARS to rapidly propagate around the globe

- Economic development; e.g. use of antibiotics to increase meat yield of farmed cows leads to antibiotic resistance

- Breakdown of public health; e.g. the current situation in Zimbabwe

- Poverty and social inequality; e.g. tuberculosis is primarily a problem in low-income areas

- War and famine

- Bioterrorism; e.g. 2001 Anthrax attacks

- Dam and irrigation system construction; e.g. malaria and other mosquito borne diseases

Both lyme disease and STARI can be treated with antibiotics, particularly doxycyclin.

The Great Imitator (also The Great Masquerader) is a phrase used for medical conditions that feature nonspecific symptoms and may be confused with a number of other diseases. Most great imitators are systemic in nature. Diseases sometimes referred to with this name include:

- Various cancers

- Intravascular large B-cell lymphoma

- Various rheumatic conditions, including:

- Fibromyalgia

- Psoriatic arthritis

- Lupus erythematosus

- Systemic lupus erythematosus

- Sarcoidosis

- Multiple sclerosis

- Celiac disease

- Addison's Disease

- Pulmonary embolism

- Various infectious diseases, including:

- Syphilis

- Lyme disease

- Nocardiosis

- Tuberculosis

- Brucellosis

- Malaria

- Breathing-related sleep disorders (chiefly sleep apnea/hypopnea and upper-airway resistance syndrome).

Tick-borne encephalitis (TBE) is a viral infectious disease involving the central nervous system. The disease most often manifests as meningitis, encephalitis, or meningoencephalitis. Although TBE is most commonly recognized as a neurological disorder, mild fever can also occur. Long-lasting or permanent neuropsychiatric consequences are observed in 10 to 20% of infected patients.

The number of reported cases has been increasing in most countries.

The tick-borne encephalitis virus is known to infect a range of hosts including ruminants, birds, rodents, carnivores, horses, and humans. The disease can also be spread from animals to humans, with ruminants and dogs providing the principal source of infection for humans.

TBE, like Lyme disease, is one of the many tick-borne diseases.

The disease is most common in Central and Eastern Europe, and Northern Asia. About ten to twelve thousand cases are documented a year but the rates vary widely from one region to another. Most of the variation is the result of variation in host population, particularly that of deer. In Austria, an extensive free vaccination program since the 1960s has reduced incidence by roughly 85%. In Sweden, most cases of TBE occur in a band running from Stockholm to the west, especially around lakes and the nearby region of the Baltic sea. This reflects the greater population involved in outdoor activities in these areas. Although in some regions of Russia and Slovenia the prevalence of cases can be as high as 70 cases per 100,000 people per year, in most regions it is far lower, and overall, for Europe the estimated risk is roughly 1 case per 10,000 human-months of woodland activity. Travelers to endemic regions do not experience many cases, with only 5 cases reported among U.S. travelers returning from Eurasia between 2000 and 2011, a rate so low that the U.S. Centers for Disease Control and Prevention recommend vaccination only for those who will be extensively exposed in high risk areas.

An emerging infectious disease (EID) is an infectious disease whose incidence has increased in the past 20 years and could increase in the near future. Emerging infections account for at least 12% of all human pathogens. EIDs are caused by newly identified species or strains (e.g. Severe acute respiratory syndrome, HIV/AIDS) that may have evolved from a known infection (e.g. influenza) or spread to a new population (e.g. West Nile fever) or to an area undergoing ecologic transformation (e.g. Lyme disease), or be "reemerging" infections, like drug resistant tuberculosis. Nosocomial (hospital-acquired) infections, such as methicillin-resistant Staphylococcus aureus are emerging in hospitals, and extremely problematic in that they are resistant to many antibiotics. Of growing concern are adverse synergistic interactions between emerging diseases and other infectious and non-infectious conditions leading to the development of novel syndemics. Many emerging diseases are zoonotic - an animal reservoir incubates the organism, with only occasional transmission into human populations.

Southern tick-associated rash illness (STARI) produces a similar rash pattern although it develops more quickly and is smaller. This erythema is also sometimes called erythema migrans or EM. The associated infectious agent has not been determined. Antibiotic treatment resolves the illness quickly.

There is currently no established treatment.

Half of all cases results in permanent neurological damage and 10-15% result in death.

"A. phagocytophilum" is transmitted to humans by "Ixodes" ticks. These ticks are found in the US, Europe, and Asia. In the US, "I. scapularis" is the tick vector in the East and Midwest states, and "I. pacificus" in the Pacific Northwest. In Europe, the "I. ricinus" is the main tick vector, and "I. persulcatus" is the currently known tick vector in Asia.

The major mammalian reservoir for "A. phagocytophilum" in the eastern United States is the white-footed mouse, "Peromyscus leucopus". Although white-tailed deer and other small mammals harbor "A. phagocytophilum", evidence suggests that they are not a reservoir for the strains that cause HGA. A tick that has a blood meal from an infected reservoir becomes infected themselves. If an infected tick then latches onto a human the disease is then transmitted to the human host and "A." "phagocytophilum" symptoms can arise.

"Anaplasma phagocytophilum" shares its tick vector with other human pathogens, and about 10% of patients with HGA show serologic evidence of coinfection with Lyme disease, babesiosis, or tick-borne meningoencephalitis.

Powassan encephalitis, caused by the Powassan virus (POWV), as flavivirus also known as the deer tick virus, is a form of arbovirus infection that results from tick bites. It can occur as a co-infection with Lyme disease since both are transmitted to humans by the same species of tick. There has been a surge in the number of cases and geographic range in the last decade. In the United States, cases have been recorded in the northeast. The disease was first isolated from the brain of a boy who died of encephalitis in Powassan, Ontario, in 1958. The disease is a zoonosis, an animal disease, usually found in rodents and ticks, with spillover transmission to humans. The virus is antigenically related to the Far Eastern tick-borne encephalitis viruses.