We examined the effectiveness and safety of the combination of rifampin plus ofloxacin given orally for treating prosthetic orthopedic implants infected with staphylococci. The prospective cohort study was conducted in a referral public hospital with ambulatory care services between 1985 and 1991. Consecutive patients from whom Staphylococcus organisms susceptible to the study drugs were isolated from their orthopedic implants and who had no contraindication to the treatment were eligible for the study. All patients were treated orally with rifampin, 900 mg/day, plus ofloxacin, 600 mg/day. Patients with hip prosthesis infection were treated for 6 months, with removal of any unstable prostheses after 5 months of treatment; patients with knee prosthesis infection were treated for 9 months, with removal of the prosthesis after 6 months of treatment; and patients with infected bone plates were treated for 6 months, with removal of the plate after 3 months of treatment, if necessary. Monthly clinical evaluations were conducted until the completion of the treatment and follow-up or telephone interviews were conducted at 6, 12, 24, 36, 48, and 60 months thereafter. Treatment failures were documented by clinical evaluation, sampling of the infected site for culture and antibiotic activity measurement, and fistulography, if possible. Cure was defined as the absence of clinical, biological, and radiological evidence of infection 6 months after the completion of treatment, treatment failure was defined as the absence of cure, and relapse was defined as the reappearance of infection caused by the same Staphylococcus isolate that caused the original infection, regardless of the timing of this secondary infection. Among 51 patients included in the study and evaluable for safety, 4 patients had side effects and were not evaluable for treatment effectiveness; the overall success rate was 74% among 47 patients, with a success rate of 81% for the hip prosthesis group, 69% for the knee prosthesis group, and 69% for the osteosynthesis device group. Eight treatment failures were relaxed to the isolation of a resistant bacterium. The combination of rifampin administered orally plus ofloxacin is a suitable alternative to the conventional long-term intravenous therapy for treatment of orthopedic implants infected with staphylococci.