Although penicillin has been the antibiotic of choice for therapy of Group A beta-hemolytic streptococcal pharyngitis for more than four decades, reports of bacteriologic and clinical treatment failures with penicillin have increased in recent years. We conducted a meta-analysis of 19 studies to examine whether oral cephalosporins were associated with lower failure rates than oral penicillin in the treatment of Group A beta-hemolytic streptococcal pharyngitis. The overall bacteriologic cure rate for penicillin was 84% (95% confidence interval (CI), 82%, 86%) compared with 92% (95% CI, 91%, 94%) among patients treated with cephalosporins (P less than 0.0001). The overall clinical cure rate in the penicillin groups was 89% (95% CI, 87%, 91%) compared with 95% (95% CI, 94%, 96%) in the cephalosporin group (P less than 0.001). There was no significant difference between the cephalosporins and the penicillins with respect to adverse events. There may be clinical circumstances in which treatment of Group A beta-hemolytic streptococcal pharyngitis with cephalosporins is indicated.