We compared phenoxymethyl penicillin, erythromycin, and tetracycline, in each instance 250 mg four times a day for 10 days, for the treatment of early Lyme disease (stage 1). None of 39 patients given tetracycline developed major late complications compared with 3 of 40 penicillin-treated patients and 4 of 29 given erythromycin (p = 0.07). However, with all three antibiotic agents, nearly half of patients had minor late symptoms. For neurologic abnormalities (stage 2), 12 patients were treated with high-dose intravenous penicillin, 20 million U a day for 10 days. Pain usually subsided during therapy, but a mean of 7 to 8 weeks was required for complete recovery of motor deficits. For the treatment of established arthritis (stage 3), 20 patients were assigned treatment with intramuscular benzathine penicillin (7.2 million U) and 20 patients received saline. Seven of the 20 penicillin-treated patients (35%) were apparently cured, but all 20 patients given placebo continued to have attacks of arthritis (P less than 0.02). Of 20 arthritis patients treated with intravenous penicillin G, 20 million U a day for 10 days, 11 (55%) were apparently cured. Thus, all 3 stages of Lyme disease can be treated with antibiotic therapy, but some patients with late disease may not respond.