The currently recommended antibiotic for treatment of fetal syphilis in pregnant women who are allergic to penicillin is erythromycin. However, clindamycin crosses the placenta more effectively than erythromycin. Therefore, an in vivo rabbit model of intradermal syphilomas was used to determine the effect of clindamycin compared with the effects of erythromycin and penicillin on the growth of virulent Treponema pallidum. The average number of motile treponemes in two, paired, mature lesions was determined before and after therapy in groups of four rabbits per dosage. Single intramuscular doses of clindamycin (15 and 40 mg/kg) and erythromycin (12 and 40 mg/kg) did not decrease treponeme counts significantly. Single injections of penicillin (10,000 units/kg) reduced treponemal counts by more than 250-fold. Multiple intramuscular injections of clindamycin reduced counts by five- to sevenfold, whereas multiple doses of erythromycin and penicillin decreased treponeme counts by greater than 300-fold. These studies indicate that clindamycin is far less active than erythromycin or penicillin in treatment of established syphilitic lesions in rabbits.