In a multicenter, open, randomized, prospective, comparative study, 28 patients with primary (n = 9) or secondary (n = 19) syphilis were treated with either ceftriaxone or penicillin G. 14 patients received ceftriaxone 4 x 1 g i.m. every 2 days. 14 other patients were treated with penicillin G 1 million IU i.m. daily for 15 days (standard therapy of primary and secondary syphilis). To avoid Herxheimer reaction we applied prednisolone 50-100 mg i.m. before specific treatment. Diagnosis was confirmed by clinical symptoms, dark-field microscopy and serological tests (VDRL titer, TPHA test and 19s-IgM-FTA-abs test or SPHA test). Follow-up examinations during therapy were repeated on days 2, 4, 6 (dark-field microscopy, physical examination) and day 14 (VDRL titer). To evaluate therapeutic efficacy, serological controls were repeated 1, 2, 3, 6 and 12 months after therapy (VDRL, SPHA). In all patients, a marked decline (minimum 2-dilution decrease) in VDRL titer and resolution of clinical symptoms were noted. An adverse reaction was seen in 1 patient of the clemizol-penicillin G group (allergic penicillin exanthema). There were no adverse reactions to ceftriaxone. Summing up, there was no detectable difference in clinical and serological response to syphilis treatment either with ceftriaxone or penicillin G. Ceftriaxone, thus can be regarded as an equivalent alternative to penicillin G in the treatment of primary and secondary syphilis.