SUMMARY A multicentre, randomised, double‐blind trial in Latin America compared oral levofloxacin 500 mg once daily for 7 days with oral ciprofloxacin 500 mg twice daily for 10 days in 272 patients with uncomplicated skin and skin structure infections. Among 253 subjects evaluable for clinical efficacy (129 levofloxacin, 124 ciprofloxacin), clinical success (cure and improvement) was observed in 96.1% of levofloxacin‐treated patients and in 93.5% of ciprofloxacin‐treated patients. Overall, bacteriological eradication rates by pathogen were 93.2% and 91.7%, respectively. Levofloxacin eradicated 94% (66/70) of Staphylococcus aureus and 94% (17/18) of Streptococcus pyogenes isolates, compared with 93% (70/75) and 92% (12/13) for ciprofloxacin. Microbiological eradication rates by subject were approximately 93% and 90% for the levofloxacin and ciprofloxacin groups, respectively. Drug‐related adverse events were reported by 8.9% of those receiving levofloxacin and 8.2% of those administered ciprofloxacin. Findings support the efficacy of oral levofloxacin for uncomplicated skin and skin structure infections due to S. aureus and S. pyogenes.