BACKGROUND: To evaluate the effectiveness of short courses of antibiotic therapy for patients with acute streptococcal pharyngitis. METHODS: Randomized controlled trials comparing short-course antibiotic therapy (≤5 days) with long-course antibiotic therapy (≥7 days) for patients with streptococcal pharyngitis were included. Two primary outcomes: early clinical cure and early bacterial eradication. RESULTS: Fifty randomized clinical trials were included. Overall, short-course antibiotic treatment was as effective as long-course antibiotic treatment for early clinical cure (odds ratio (OR) 0.85; 95% confidence interval (CI) 0.79 to 1.15). Subgroup analysis showed that short-course penicillin was less effective for early clinical cure (OR 0.43; 95% CI, 0.23 to 0.82) and bacteriological eradication (OR 0.34; 95% CI, 0.19 to 0.61) in comparison to long-course penicillin. Short-course macrolides were equally effective, compared to long-course penicillin. Finally, short-course cephalosporin was more effective for early clinical cure (OR 1.48; 95% CI, 1.11 to 1.96) and early microbiological cure (OR 1.60; 95% CI, 1.13 to 2.27) in comparison to long-course penicillin. In total, 1211 (17.7%) participants assigned to short-course antibiotic therapy, and 893 (12.3%) cases assigned to long-course, developed adverse events (OR 1.35; 95% CI, 1.08 to 1.68). CONCLUSIONS: Macrolides and cephalosporins belong to the list of “Highest Priority Critically Important Antimicrobials”; hence, long-course penicillin V should remain as the first line antibiotic for the management of patients with streptococcal pharyngitis as far as the benefits of using these two types of antibiotics do not outweigh the harms of their unnecessary use.