BACKGROUND: Oral combination therapy with fluoroquinolones plus rifampicin is a promising alternative to standard parenteral therapy for staphylococcal infections. METHODS: In a multicenter, randomized trial, we compared the efficacy, safety, and length of hospital stay for patients with staphylococcal infections treated either with an oral combination of a fluoroquinolone (fleroxacin) plus rifampicin or with standard parenteral treatment (flucloxacillin or vancomycin). Patients were included if cultures showed the presence of bacteremia or deep-seated infections with Staphylococcus aureus (104 patients) or catheter-related bacteremia due to drug-susceptible, coagulase-negative staphylococci (23 patients). RESULTS: The cure rate in the intention-to-treat analysis was 78% for the fleroxacin-rifampicin group (68 patients) and 75% for the standard therapy group (59 patients; 47 received flucloxacillin, and 12 received vancomycin); in the population of clinically evaluable patients (n=119), the cure rate was 82% and 80%, respectively; and in the population of microbiologically evaluable patients (n=103), the cure rate was 86% and 84%, respectively. Clinical and bacteriological failures after S. aureus infections were documented in similar proportions of patients. The median length of hospital stay after study entry was 12 days in the fleroxacin-rifampicin group, compared with 23 days in the standard treatment group (P=.006). More adverse events probably related to the study drug were reported in the fleroxacin-rifampicin group than in the standard therapy group (15 of 68 vs. 5 of 59 patients; P=.05). CONCLUSIONS: This study suggests that an oral regimen containing a fluoroquinolone plus rifampicin may be effective for treating staphylococcal infections, allowing earlier discharge from the hospital.