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We conducted a meta-analysis of 9 randomized controlled trials (involving 2113 patients) comparing cephalosporins with penicillin for treatment of group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis in adults. The summary odds ratio (OR) for bacteriologic cure rate significantly favored cephalosporins, compared with penicillin (OR,1.83; 95% confidence interval [CI], 1.37–2.44); the bacteriologic failure rate was nearly 2 times higher for penicillin therapy than it was for cephalosporin therapy (P = .00004). The summary OR for clinical cure rate was 2.29 (95% CI, 1.61–3.28), significantly favoring cephalosporins (P < .00001). Sensitivity analyses for bacterial cure significantly favored cephalosporins over penicillin in trials that were double-blinded and of high quality, trials that had a well-defined clinical status, trials that performed GABHS serotyping, trials that eliminated carriers from analysis, and trials that had a test-of-cure culture performed 3–14 days after treatment. This meta-analysis indicates that the likelihood of bacteriologic and clinical failure in the treatment of GABHS tonsillopharyngitis is 2 times higher for oral penicillin than for oral cephalosporins.