Background Periprosthetic joint infection after TKA is a challenging complication. Two-stage exchange arthroplasty is the accepted standard of care, but reported failure rates are increasing. It has been suggested this is due to the increased prevalence of methicillin-resistant infections. Questions/purposes We asked the following questions:(1) What is the reinfection rate after two-stage exchange arthroplasty? (2) Which risk factors predict failure? (3) Which variables are associated with acquiring a resistant organism periprosthetic joint infection? Methods This was a case-control study of 102 patients with infected TKA who underwent a two-stage exchange arthroplasty. Ninety-six patients were followed for a minimum of 2 years (mean, 34.5 months; range, 24-90