Twelve patients were treated with high-dose intravenous penicillin for neurologic abnormalities of Lyme disease. Headache, stiff neck, and radicular pain usually began to subside by the second day of therapy and were often gone by 7 to 10 days. Five of the 12 patients continued to have intermittent mild headache for several more weeks, but no patient relapsed after therapy was stopped. Compared to 15 previous patients treated with prednisone alone, the duration of meningitic syndrome was significantly shorter in those given penicillin (mean duration, 1 versus 29 weeks, p less than 0.000001). However, in both groups, a mean of 7 to 8 weeks was required for complete recovery of motor deficits. Despite antibiotic therapy, 3 of the 12 patients treated with penicillin continued to have frequent arthralgias, musculoskeletal pain, and fatigue. We conclude that high-dose intravenous penicillin is effective therapy for neurologic abnormalities of Lyme disease.