In a double-blind, prospective, randomized, multicenter study, 164 patients with a clinical and bacteriologic diagnosis of acute streptococcal tonsillitis/pharyngitis were enrolled to compare the efficacy and safety of two regimens of clindamycin. A rapid identification test of Group A betahemolytic streptococci (GABHS) was used to initiate the therapy; however, a positive tonsillar/pharyngeal culture was required at pretreatment to determine if the patient was assessable. Another culture was repeated at least 2 days after the 10 days of drug therapy. From 164 patients enrolled (mean age, 27.7 years; range, 14 to 60 years), 141 were assessable for efficacy; 22 patients were excluded because they did not have a positive culture at pretreatment and 1 patient did not complete the study due to a side effect (rash). All patients were included in the safety analysis. Patients received either clindamycin hydrochloride capsules 150 mg four times per day (QID) or clindamycin hydrochloride capsules 300 mg two times per day (BID) and placebo capsules BID for 10 days. There were no significant differences between groups in terms of demographics, medical history, and evolution of symptoms. The clinical efficacy rate in the two groups at day 12 was as follows: QID group—cured, 64 (92.8%) of 69 patients; improved, 5 (7.2%) of 69 patients; BID group—cured, 67 (93.1%) of 72 patients; improved, 5 (6.9%) of 72 patients. There were no significant differences between the groups. Both regimens were well tolerated with only 1 patient in the QID group who did not complete the therapy due to a rash. The GABHS were eradicated in 66 (96%) of 69 patients in the QID group and in 70 (97%) of 72 patients in the BID group. In conclusion, this study showed that clindamycin hydrochloride administered BID (300 mg every 12 hours) had a rate of clinical and microbiologic efficacy similar to the standard clindamycin regimen (150 mg QID), and a similar safety profile in patients with acute streptococcal tonsillitis/pharyngitis.