The activity of ceftriaxone, a newly developed cephalosporin, against early cutaneous infections with Treponema pallidum in rabbits was compared with that of equimolar doses of penicillin G. Activity was related to the time required for cutaneous lesions to become dark-field negative, serological response, and the disappearance of T. pallidum from the popliteal lymph nodes. Both antibiotics were very effective in the treatment of syphilis in this animal model. The 50% curative dose for penicillin G was 0.8 mumol/kg (0.29 mg or 480 U/kg) and for ceftriaxone, it was 1.45 mumol/kg (0.96 mg/kg). Overall, ceftriaxone was slightly less effective than penicillin G was. Transmission and scanning electron microscopy studies of testicular aspirates obtained from rabbits treated with ceftriaxone revealed alterations in the treponeme surface which apparently resulted in changes in cell permeability and morphology.