The low responsiveness of Lyme arthritis to high dose intravenous penicillin G therapy has evoked the demand for new drugs for the treatment of late stage borreliosis. As can be deduced from in vitro susceptibility data, third generation cephalosporins are far more effective on Borrelia burgdorferi spirochetes than penicillin G. The study presented here was designed to compare cefotaxime at a dosage of 2 x 3 g/day with penicillin G at a dosage of 2 x 10 megaunits/day, for ten days in a prospective randomized trial. A total of 135 patients were included in the study. They were diagnosed to suffer from late stage Lyme borreliosis on the basis of defined clinical symptoms compatible with stage three borreliosis manifestations of at least six months' duration and positive antibody titers against B. burgdorferi. Final outcomes were recorded after a 24 month post-treatment observation period with re-examination at three-month-intervals. Cefotaxime proved to be significantly superior to penicillin G with 87.9% versus 61.3% of treatments resulting in full or incomplete remission of symptoms (p = 0.002). Clinical remission was accompanied by declining antibody titers. Herxheimer-like reactions were observed in 20% of the patients of the penicillin group and in 40.5% of the patients of the cefotaxime group and may be interpreted as an indication of a response to therapy.