The aim of this prospective, blinded, randomized study was to demonstrate the efficacy and safety of oral azithromycin and dicloxacillin in the treatment of adults with acute skin and skin-structure infections. Sixty-two patients were included in the intent-to-treat group and 60 were evaluable for analysis. Azithromycin was given as a 500 mg once-daily dose for three days and dicloxacillin as 250 mg qid for seven days. Isolated pathogens included primarily Staphylococcus aureus, Streptococcus spp., and coagulase-negative staphylococci. Clinical resolution was 83.3% in the azithromycin group and 83.9% in the dicloxacillin group, with bacteriological eradication of 90.0% in the azithromycin group and 87.1% in the dicloxacillin group. Persistence of infection was recorded in one patient in the dicloxacillin group and superinfection in one patient in the azithromycin group. Azithromycin appears to be a safe and effective antibiotic for the treatment of adult patients with acute skin and skin-structure infections.