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Background Long-term reinfection and mortality rates and clinical outcomes with sufficient subject numbers remain limited for patients undergoing two-stage exchange arthroplasty for chronic periprosthetic knee infections. The purpose of this study was to determine the long-term reinfection, complication, and mortality following reimplantation for two-stage exchange following knee arthroplasty. Methods Retrospective review of 178 patients who underwent two-stage exchange knee arthroplasty for chronic PJI at three large tertiary referral institutions with an average of 6.63-year follow-up from reimplantation from 1990 to 2015. Rates of reinfection, mortality, and all-cause revision were calculated along with the cumulative incidence of reinfection with death as a competing factor. Risk factors for reinfection were determined using Cox multivariate regression analysis. Results Overall rate of infection eradication was 85.41%, with a mortality rate of 30.33%. Patients with minimum 5-year follow-up (n = 118, average 8.32 years) had an infection eradication rate of 88.98%, with a mortality rate of 33.05%. Conclusion This is a large series with long-term follow-up evaluating outcomes of two-stage exchange knee arthroplasty resulting in adequate infection eradication and high mortality. Results were maintained at longer follow-up. This technique should be considered in patients with chronic PJI; however, realistic expectations regarding long-term outcomes must be discussed with patients.