During 1980 and 1981, we compared antibiotic regimens in 108 adult patients with early Lyme disease. Erythema chronicum migrans and its associated symptoms resolved faster in penicillin- or tetracycline-treated patients than in those given erythromycin (mean duration, 5.4 and 5.7 versus 9.2 days, F = 3.38, p < 0.05). None of 39 patients given tetracycline developed major late complications (meningoencephalitis, myocarditis, or recurrent attacks of arthritis) compared with 3 of 40 penicillin-treated patients and 4 of 29 given erythromycin (chi square with 2 degrees of freedom = 5.33, p = 0.07). In 1982, all 49 adult patients were given tetracycline; again, none of them developed major complications. However, with all three antibiotic agents nearly half of the patients had minor late symptoms such as headache, musculoskeletal pain, and lethargy. These complications correlated significantly with the initial severity of illness. For patients with early Lyme disease, tetracycline appears to be the most effective drug, then penicillin, and finally erythromycin.