In the United States, intermittent or chronic mono- or oligoarthritis, particularly affecting the knee, is the most common manifestation of late Lyme disease (LD). Lyme arthritis (LA) can usually be prevented by early treatment of acute LD. However, the erythema migrans rash may go undetected in children and in the dark skin of African Americans, leading to delayed treatment and a relatively increased incidence in LA. Virtually all untreated patients with LA have high levels of serum immunoglobulin G antibodies, and sometimes low levels of immunoglobulin M antibodies, to Borrelia burgdorferi (Bb) by ELISA and Western blot. These responses may persist for many years after antibiotic treatment, and therefore, serologic results do not accurately distinguish between active or past infection. Most patients with LA respond well to standard courses of antibiotic treatment, but a small percentage have persistent knee synovitis, in some cases possibly related to the triggering of intrasynovial autoimmunity. Other patients develop a syndrome of diffuse arthralgia, myalgia, fatigue, and subjective cognitive difficulty during or soon after LD, which persists despite antibiotic treatment. Patients with this post-treatment, post-LD syndrome were recently studied in a placebo-controlled double-blind antibiotic trial. There was no evidence of Borrelial infection in these patients by culture or detection of Bb DNA in blood or spinal fluid. Furthermore, there was no difference in responsiveness of these patients to a 3-month course of antibiotic compared with placebo treatment. Thus, LA caused by active Bb infection, post-treatment LA with persistent knee synovitis and post-LD syndrome are distinct and distinguishable clinical entities.