The purpose of this prospective, randomized clinical trial was to investigate the relative efficacy of cefadroxil and penicillin V in the treatment of group A streptococcal (GAS) pharyngitis and to clarify the mechanism(s) responsible for antimicrobial treatment failures in GAS pharyngitis. Children between 3 and 18 years of age who presented to one of four private pediatric offices in Danbury, CT, Bristol, CT, Albany, NY, and Valparaiso, IN with acute pharyngitis and a positive throat culture for GAS were randomly assigned to receive either cefadroxil or penicillin V orally for 10 days. Throat swabs were obtained before and 2 to 12 days following the completion of therapy for the isolation of GAS and for the evaluation of the normal pharyngeal flora for beta-lactamase and bacteriocin activity. Enrolled patients were classified on the basis of the presence or absence of certain clinical findings as being more likely to have bona fide acute GAS pharyngitis or more likely to be a chronic carrier of GAS with an intercurrent viral illness. Bacteriologic treatment success was defined as eradication of the original serotype of GAS on the follow-up throat culture. Of the 462 patients enrolled, 374(81%) (187 cefadroxil, 187 penicillin V) were assessed to be compliant and were evaluable. The bacteriologic treatment success rates for the patients in the cefadroxil and penicillin groups were 94% and 86%, respectively (p<.01). However, among the patients classified clinically as likely to have bona fide infection with GAS, there was no difference in the bacteriologic treatment success rates in the cefadroxil and penicillin groups (95% and 94%, respectively). Among the patients classified clinically as likely to be streptococcal carriers, bacteriologic treatment success rates in the cefadroxil and penicillin groups were 92% and 73%, respectively (p<.01). The presence or absence of beta-lactamase and/or bacteriocin-producing pharyngeal flora had no consistent effect on the bacteriologic eradication rates among the patients in any group (penicillin or cefadroxil treatment groups; patients classified clinically as either having GAS pharyngitis or streptococcal carriage). In conclusion, neither beta-lactamase nor bacteriocin produced by normal pharyngeal flora is related to bacteriologic treatment failures in GAS pharyngitis. Cefadroxil is more effective than penicillin V in eradicating GAS from patients likely to be streptococcal carriers. However, among patients likely to have bona fide acute GAS pharyngitis, the effectiveness of cefadroxil and penicillin V are comparable.