The success of open irrigation and debridement with component retention (ODCR) for acute periprosthetic knee joint infection varies widely. The species and virulence of the infecting organism have been shown to influence outcome. This multicenter, retrospective study identified 19 cases of acute periprosthetic methicillin-resistant Staphylococcus aureus (MRSA) knee infections managed by ODCR and at least 4 weeks of postoperative intravenous vancomycin therapy. At minimum follow-up of 2 years, the treatment failed to eradicate the infection in 16 cases (84% failure rate). Of those 16 failures, 13 patients required a 2-stage exchange arthroplasty, 2 patients required repeat incision and debridement with antibiotic suppression, and 1 patient died of MRSA sepsis. In addition, a systematic review of the literature revealed failure to eradicate infection in 10 of 13 patients managed with a similar protocol. The total success rate of ODCR in acute periprosthetic MRSA knee infection was 18%.