The purpose of this study was to determine the clinical and microbiological risk factors for treatment failure of methicillin-resistant Staphylococcus aureus (MRSA) orthopedic device-related infection (ODRI). A retrospective cohort study of patients with MRSA ODRI who were treated at Geneva University Hospitals between 2000 and 2008 was undertaken. Stored MRSA isolates were retrieved for genetic characterization and determination of the vancomycin minimum inhibitory concentration (MIC). Fifty-two patients were included, of whom 23 (44%) had joint arthroplasty and 29 (56%) had osteosynthesis. All 41 of the retrieved MRSA isolates were susceptible to vancomycin (MIC <or= 2 mg/L) and 35 (85%) shared genetic characteristics of the South German clone (ST228). During a median follow-up of 391 days (range, 4-2,922 days), 18 patients (35%) experienced treatment failure involving MRSA persistence or recurrence. Microbiological factors such as infection with the predominant clone and a vancomycin MIC of 2 mg/L were not associated with treatment failure. Using a Cox proportional hazards model, implant retention (hazard ratio [HR], 4.9; 95% confidence interval [CI], 1.3-18.2; P = 0.017) and single-agent antimicrobial therapy (HR, 4.4; 95% CI, 1.2-16.3; P = 0.025) were independent predictors of treatment failure after debridement. Therapy using a combination of antimicrobials should be considered for patients with MRSA ODRI, especially when implant removal is not feasible.