Orally administered clindamycin and penicillin were compared for effectiveness in preventing streptococcal infections in 202 randomly assigned patients with previous rheumatic fever (RF). Among 143 patients aged 21 years or younger observed for 537 patient-years, the number of streptococcal infections (and number per patient-year) was 23 (0.084) in the penicillin group and 12 (0.045) in the clindamycin group. Excluding uncooperative patients, the rate of streptococcal infection remained less, though not statistically significant, in the clindamycin group than in the penicillin group. Two RF recurrences occurred in the penicillin group, and no recurrence occurred in the clindamycin group. Clindamycin was well tolerated except for possible mild gastrointestinal symptoms in six patients. Clindamycin can be substituted for penicillin for RF prophylaxis when there is allergy to penicillin or concern about the development of penicillin-resistant mouth organisms.