We examined the effectiveness and safety of high-dose oral co-trimoxazole (trimethoprim-sulfamethoxazole) for the treatment of orthopedic implants infected with multidrug-resistant Staphylococcus species. The prospective study was conducted between 1989 and 1997 in a university medical center with ambulatory-care services. Patients eligible for the study consisted of those from whom multidrug-resistant Staphylococcus spp. organisms susceptible only to glycopeptides and co-trimoxazole were isolated from their orthopedic implants and for whom there was no contraindication to the treatment. All patients were treated orally with high-dose co-trimoxazole (trimethoprim, 20 mg/kg of body weight/day; sulfamethoxazole, 100 mg/kg/day). Patients with prosthetic hip infections were treated for 6 months, with removal of any unstable prosthesis after 5 months of treatment; patients with prosthetic knee infections were treated for 9 months, with removal of any unstable prosthesis after 6 months of treatment; and patients with infected osteosynthetic devices were treated for 6 months, with removal of the device after 3 months of treatment, if necessary. Monthly clinical evaluations were conducted until the completion of the treatment, and follow-up examinations were conducted regularly for up to 6 years. The overall treatment success rate was 66.7% (26 of 39 patients), with success rates of 62.5% for patients with prosthetic knee infections, 50% for those with prosthetic hip infections, and 78.9% for those with other device infections. Seventeen of the 28 (60.7%) patients who did not have any orthopedic material removed were cured. Eight patients stopped the treatment because of side effects, and one patient was not compliant. In three patients treatment failed because of the appearance of a resistant bacterium. Long-term oral ambulatory treatment with co-trimoxazole appears to be an effective alternative to the conventional medicosurgical treatment of chronic multidrug-resistant Staphylococcus-infected orthopedic implants which includes long-term intravenous antibiotic therapy combined with surgical debridement and removal of foreign material or its subsequent one- or two-stage replacement.