This randomized, third-party-blinded study compared short-course therapy of once-daily azithromycin (500 mg on day 1, followed by 250 mg/day on days 2-5) with cephalexin (500 mg twice daily for 10 days) in the treatment of patients with skin and skin structure infections. At 25 centers, a total of 361 patients were entered into the study and 148 were evaluable for efficacy. The main causative pathogens, Staphylococcus aureus and Streptococcus pyogenes, were responsible for approximately two thirds of the infections in the two treatment groups. Clinical cure and improvement rates for the two treatments were comparable; 99% with azithromycin and 96% with cephalexin. On completion of therapy, both treatments had eradicated approximately 98% of pathogens. In general, both agents were well-tolerated. The results of this study show that a 5-day course of once-daily treatment with azithromycin is as effective as a 10-day course of twice-daily treatment with cephalexin in the management of skin and skin structure infections.