The ability of azithromycin, erythromycin, clarithromycin, or cefuroxime to modify the course of group A streptococcus (GAS) or Staphylococcus aureus soft-tissue infection was compared in a mouse model. In GAS-infected mice given azithromycin, fewer demonstrated dermonecrosis (P = 0.0004); the average weight gain was greater (P < 0.05) and the latency to sustained weight gain was shorter (P < 0.05) than for animals given other antibiotics. All antibiotics were effective against S. aureus infections, with no significant differences among treatments in parameters evaluated. The effectiveness of azithromycin in GAS-infected mice may be related to the high and sustained tissue concentrations achieved with this antibiotic.