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Objective: To investigate the relative efficacy of orally administered cefadroxil and penicillin V in the treatment of group A streptococcal (GABHS) pharyngitis and the mechanism(s) responsible for failure of antimicrobial therapy to eradicate GABHS from the pharynx., Study Design: A prospective, randomized clinical trial was conducted in four pediatric offices in which 462 patients with acute pharyngitis and positive culture for GABHS were randomly assigned to receive cefadroxil (n = 232) or penicillin V (n = 230)., Results: Bacteriologic treatment success rates for patients in cefadroxil and penicillin groups were 94% and 86%, respectively. However, among patients classified clinically as likely to have bona fide GABHS pharyngitis, there was no difference in bacteriologic treatment success rates in cefadroxil and penicillin groups (95% and 94%, respectively). Among patients classified clinically as likely to be streptococcal carriers, bacteriologic treatment success rates in cefadroxil and penicillin groups were 92% and 73%, respectively. The presence of beta-lactamase and/or bacteriocin-producing pharyngeal flora had no consistent effect on bacteriologic eradication rates among patients in either penicillin or cefadroxil treatment groups or among patients classified as having either GABHS pharyngitis or streptococcal carriage., Conclusions: Neither beta-lactamase nor bacteriocin produced by normal pharyngeal flora are related to bacteriologic treatment failures in GABHS pharyngitis. Cefadroxil seems to be more effective than penicillin V in eradicating GABHS from patients classified as more likely to be streptococcal carriers. However, among patients we classified as more likely to have bona fide GABHS pharyngitis, the effectiveness of cefadroxil and penicillin V seems to be comparable.