An orally administered antimicrobial regimen for the treatment of pharyngitis caused by group A beta-hemolytic streptococci that could be given once daily and for less than 10 days would be convenient and might improve compliance, decrease cost, and result in fewer side effects compared with a regimen given multiple times daily for 10 days. Previous attempts to administer oral penicillin once daily or for less than 10 days were not successful. Several cephalosporins and azithromycin have been reported to be effective when administered once daily or for less than 10 days. However, large, comprehensive studies have not been performed. In addition, the spectra of these cephalosporins and azithromycin are much broader than that of penicillin, and, even when they are administered for short courses, they are more expensive. Therefore, these novel regimens cannot be endorsed and should not supplant penicillin as the agent of choice. In contrast, once-daily amoxicillin therapy appears to be effective, is inexpensive, and has a narrower spectrum of antimicrobial activity; if these findings are confirmed by additional investigations, it could become an alternative regimen for the treatment of pharyngitis caused by group A beta-hemolytic streptococci.