We previously demonstrated that chronic pharyngeal carriage of group A beta-hemolytic streptococci (GABHS) can be terminated by intramuscular administration of benzathine penicillin plus 4 days of orally administered rifampin. Because an effective oral regimen would be desirable, we compared clindamycin with P + R for treating GABHS carriage. Healthy, symptom-free GABHS carriers were randomly assigned to receive orally administered clindamycin (20 mg/kg per day) three times a day for 10 days or intramuscularly administered benzathine penicillin with oral doses of rifampin (20 mg/kg per day) twice a day for 4 days. Compliance was documented by antibiotic activity in urine. Throat cultures for GABHS were obtained every 3 weeks for up to 9 weeks after treatment. Patients who had positive throat cultures for their original GABHS T type 3 weeks after randomization were crossed over to the other treatment. Treatment success was defined as eradication of the original GABHS T type, with all follow-up cultures negative. Clindamycin eradicated carriage in 24 (92%) of 26 patients; penicillin plus rifampin was effective in 12 (55%) of 22 patients (p less than 0.025). Including patients crossed over 3 weeks after enrollment, clindamycin was effective in 28 (85%) of 33 treatment courses compared with 12 of 22 courses of penicillin plus rifampin (p less than 0.05). We conclude that 10 days of oral clindamycin therapy was significantly more effective than benzathine penicillin plus 4 days of orally administered rifampin for treatment of symptom-free GABHS carriers.