Lyme disease is a multisystem disorder caused by a tick-transmitted spirochete, Borrelia burgdorferi. The diagnosis is based on clinical findings in most patients, particularly those with erythema migrans or exposure to geographic locations endemic for the disease. Detection of a specific antibody to B. burgdorferi is a useful confirmatory test in many patients. In atypical cases, however, a positive test result can be pivotal for determining the diagnosis and can lead to institution of definitive treatment. Serologic testing should not be used indiscriminately to diagnose Lyme disease or as the sole basis for administration of antibiotic therapy.