Background: Irrigation and débridement is an attractive low morbidity solution for acute periprosthetic knee infection. However, the failure rate in the literature is high, averaging 68% (range, 61%-82%). Patients who fail subsequently undergo two-stage reimplantation after a prolonged period of illness. This leads to higher surgical risk and further delays in rehabilitation and may contribute to failure of subsequent revision surgery. Questions/purposes: We determined the rerevision rate due to infection after two-stage reimplantation performed for failed irrigation and débridement of infected TKA. Methods: We performed a multicenter retrospective review of periprosthetic knee infections treated with a two-stage procedure from 1994 to 2008. Selection criteria for the study included initial treatment with irrigation and débridement and subsequent two-stage revision surgery. Failure of two-stage revision was defined as the need for any additional surgery due to infection. Results: Of the 83 knees that had undergone previous irrigation and débridement, 28 (34%) failed subsequent two-stage revision and required reoperation for persistent infection. Conclusions: The failure rate in this series of two-stage revisions for periprosthetic knee infection in patients treated with previous irrigation and débridement is considerably higher than previously reported failure rates of two-stage revision. Factors affecting the failure rate may include host quality, thoroughness of débridement, and organism virulence. Patients and surgeons must understand that irrigation and débridement, while initially attractive, may lead to high failure rates of subsequent two-stage reimplantation. Level of Evidence: Level III, therapeutic study. See the guidelines online for a complete description of level of evidence.