BACKGROUND: Two-stage exchange arthroplasty after a previous, failed 2-stage exchange procedure is fraught with difficulties, and there are no clear guidelines for treatment or prognosis given the heterogeneous group of patients in whom this procedure has been performed. The Musculoskeletal Infection Society (MSIS) staging system was developed in an attempt to stratify patients according to infection type, host status, and local soft-tissue status. The purpose of this study was to report the results of 2-stage exchange arthroplasty following a previous, failed 2-stage exchange protocol for periprosthetic knee infection as well as to identify risk factors for failure. METHODS: We retrospectively identified 45 patients who had undergone 2 or more 2-stage exchange arthroplasties for periprosthetic knee infection from 2000 to 2013. Patients were stratified according to the MSIS system, and risk factors for failure were analyzed. The minimum follow-up was 2 years (mean, 6 years; range, 24 to 132 months). RESULTS: At the time of follow-up, twenty-two (49%) of the patients had undergone another revision due to infection and 28 (62%) had undergone another revision for any reason. The infection recurred in 6 (75%) of 8 substantially immunocompromised hosts (MSIS type C) and in 3 (30%) of 10 uncompromised hosts (type A) following the second 2-stage exchange arthroplasty (p = 0.06). The infection recurred in 4 (80%) of 5 patients with compromise of the extremity (MSIS type 3) and 3 (33%) of 9 patients with an uncompromised extremity (type 1) (p = 0.27). Both extremely compromised hosts with an extremely compromised extremity (type C3) had recurrence of the infection whereas 3 (30%) of the 10 uncompromised patients with no or less compromise of the extremity (type A1 or A2) did. Five patients in the failure group underwent a third 2-stage exchange arthroplasty following reinfection, and 3 of them were infection-free at the time of the latest follow-up. CONCLUSIONS: Uncompromised hosts (MSIS type A) with an acceptable wound (MSIS type 1 or 2) had a 70% rate of success (7 of 10) after a repeat 2-stage exchange arthroplasty, whereas type-B2 hosts had a 50% success rate (10 of 20). The repeat 2-stage exchange procedure failed in both type-C3 hosts; thus, alternative salvage procedures should be considered for such patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.