We studied six patients with central nervous system manifestations of Lyme disease. Weeks to years after the initial infection, behavioral changes, ataxia, and/or weakness in bulbar or peripheral muscles developed. Four of the six patients had a lymphocytic pleocytosis in the cerebrospinal fluid, and two of them had magnetic resonance imaging scans suggestive of demyelination. In a patient with a subacute encephalitis, a brain biopsy specimen showed microgliosis without an inflammatory infiltrate and spirochetes morphologically compatible with Borrelia burgdorferi. All six patients had elevated antibody titers to B burgdorferi in serum, but none had selective concentration of specific antibody in the cerebrospinal fluid. All six patients were treated with high-dose intravenous penicillin; four had complete recoveries and two did not. Lyme disease may affect the central nervous system causing organic brain disease or syndromes suggestive of demyelination.