The outcome of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis may differ between Europe and the USA. In the present study, Medline, Embase, reference lists, and abstract searches were used to identify randomized, controlled trials of cephalosporin versus penicillin treatment of group A streptococcal (GAS) tonsillopharyngitis. The outcomes of interest were bacteriologic and clinical cure rates from investigations conducted in Europe versus those conducted in the USA. Forty-seven trials involving 11,426 patients were included in the meta-analyses. For the comparison of 10 days of treatment with cephalosporins versus 10 days of treatment with penicillin, there were ten European and 25 U.S. trials, all involving pediatric subjects. The overall odds ratio (OR) favored cephalosporins more strongly in bacteriologic cure rate in Europe (OR=4.27, p<0.00001) than in the USA (OR=2.70, p<0.00001). Studies of 4-5 days of cephalosporin treatment versus 10 days of penicillin treatment were also analyzed. For nine European trials, the OR significantly favored cephalosporins (OR=1.30, p=0.03) in bacteriologic cure rates, but not as strongly as in the USA, (OR=2.41, p<0.00001). When results for 4-5 days of cephalosporin treatment were divided into pediatric versus adult populations, the differences in bacteriologic eradication rates obtained with cephalosporins were more pronounced in children. The likelihood of bacteriologic and clinical failure of GAS tonsillopharyngitis treatment in both European and U.S. patients is significantly less if a 10-day course of oral cephalosporin is prescribed, and is at least similar, if not significantly less, with a 4- to 5-day course of oral cephalosporin compared with a 10-day course of oral penicillin.