The management of prosthetic joint infections remains a clinical challenge, particularly infections due to methicillin-resistant staphylococci. Previously, this infection was considered a contraindication to debridement and retention strategies. This retrospective cohort study examined the treatment and outcomes of patients with arthroplasty infection by methicillin-resistant staphylococci managed by debridement and retention in conjunction with rifampin-fusidic acid combination therapy. Over an 11-year period, there were 43 patients with infection by methicillin-resistant staphylococci managed with debridement and retention. This consisted of close-interval repeated arthrotomies with pulsatile lavage. Rifampin was combined with fusidic acid for the majority of patients (88%). Patients were monitored for a median of 33.5 months (interquartile range, 20 to 54 months). Overall, 9 patients experienced treatment failure, with 12- and 24-month estimates of infection-free survival of 86% (95% confidence interval [CI], 71 to 93%) and 77% (95% CI, 60 to 87%), respectively. The following factors were associated with treatment failure: methicillin-resistant Staphylococcus aureus (MRSA) arthroplasty infection, a single surgical debridement or ≥4 debridements, and the receipt of less than 90 days of antibiotic therapy. Patients with infection by methicillin-resistant coagulase-negative staphylococci (MR-CNS) were less likely to fail treatment. The overall treatment success rate reported in this study is comparable to those of other treatment modalities for prosthetic joint infections by methicillin-resistant staphylococci. Therefore, the debridement and retention of the prosthesis and rifampin-based antibiotic therapy are a valid treatment option for carefully selected patients.