The purpose of this study was to compare the safety and efficacy of lomefloxacin with that of cefaclor in the treatment of adult secondary bacterial skin and skin structure infections. The study was conducted as a randomized, single-blind comparison. Eighty patients enrolled in the study, of which 74 were evaluable: 37 patients in the lomefloxacin group and 37 in the cefaclor group. Patients received either 400 mg of lomefloxacin orally once daily or 250 mg of cefaclor orally three times daily for 12 days. The most frequent pathogens isolated included Staphylococcus aureus, Streptococcus pyogenes, coagulase-negative staphylococci, and Escherichia coli. The clinical response was similar in both groups (89.1%). The bacteriologic eradication rate was 100% in the lomefloxacin group and 94.5% in the cefaclor group. Adverse events were minimal. Once-daily lomefloxacin is a safe and effective treatment for secondary bacterial skin and skin structure infections caused by susceptible pathogens.