In a single-blind, placebo-controlled randomized trial, 100 successive patients were enrolled with serious skin and soft-tissue infections, whose illnesses had precipitated an initial hospital admission or an extension of inpatient care. There were 93 evaluable patients who received either ofloxacin, 400 mg orally every 12 hours plus an intravenously administered placebo every eight hours, or cefotaxime, 2.0 g intravenously every eight hours plus an orally administered placebo every 12 hours. The average length of therapy was 12 days. Both patient groups had similar demographics and underlying conditions. Wound infection was the most common diagnosis, followed by abscess, cellulitis, and trophic ulcer. Multiple pathogens were commonly isolated from infected sites (1.4 pathogens/patient). The most common pathogen was Staphylococcus aureus, followed by Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Serratia marcescens, Proteus/Providencia spp., and Enterobacter spp. Persistence of the initial pathogen at the end of therapy was observed in 22.5 percent of the cefotaxime-treated group, but in only 10 percent of the ofloxacin-treated group. There was one clinical failure in the cefotaxime group, caused by a susceptible strain of Enterobacter cloacae, and there was one clinical failure in the ofloxacin group, in which the patient had an Acinetobacter calcoaceticus var. anitratus wound infection and subsequently developed a P. aeruginosa superinfection. Adverse experiences, including rash, insomnia, and nausea, occurred in 16 percent of the patients in each group. It was concluded that oral ofloxacin is as safe and efficacious as parenteral cefotaxime in the treatment of serious skin and skin structure infections.