In a randomized investigator-blinded study, 506 children ages 6 months to 12 years with positive rapid direct antigen tests for Group A beta-hemolyticStreptococcus(GABHS) received treatment with either clarithromycin suspension, 7.5 mg/kg twice daily, or penicillin VK suspension, 13.3 mg/kg three times per day for 10 days. Signs and symptoms of pharyngitis or tonsillitis were evaluated and throat cultures were obtained before treatment, once during treatment and 4 to 6 days and 19 to 25 days posttreatment. All GABHS isolates were susceptiblein vitroto clarithromycin. Successful clinical responses at the end of treatment were demonstrated in 169 of 176 (96%) evaluable clarithromycin-treated patients and 179 of 191 (94%) evaluable penicillin-treated patients. GABHS was successfully eradicated at end of treatment in 168 of 183 (92%) evaluable clarithromycintreated patients compared with 162 of 199 (81%) evaluable penicillin-treated patients (P= 0.004).There were no significant changes in hematologic or serum chemistry parameters in either group. Both drugs were well-tolerated. The incidence and nature of adverse events were similar in the clarithromycin and penicillin groups, except for gastrointestinal complaints reported in 35 of 250 (14%) clarithromycin recipients compared with 12 of 256 (5%) penicillin recipients (P≤ 0.001). The results indicate that twice daily clarithromycin was as safe and effective as three times daily penicillin VK in the treatment of children with streptococcal pharyngitis or tonsillitis. Clarithromycin was statistically superior to penicillin VK in the eradication of GABHS.