Background: The diagnosis of periprosthetic joint infection (PJI) continues to pose a challenge. While many diagnostic criteria have been proposed, a gold standard for diagnosis is lacking. Use of multiple diagnostic criteria within the joint arthroplasty community raises concerns in patient treatment and comparison of research pertaining to PJI. Questions/purposes: We (1) determined the variation in existing diagnostic criteria, (2) compared the existing criteria to a proposed new set of criteria that incorporates aspirate cell count analysis, and (3) investigated the variations between the existing criteria and the proposed criteria. Patients and Methods: We retrospectively identified 182 patients undergoing 192 revision knee arthroplasties who had a preoperative joint aspiration analysis at our institution between April 2002 and November 2009. We excluded 20 cases due to insufficient laboratory parameters, leaving 172 cases for analysis. We applied six previously published sets of diagnostic criteria for PJI to determine the variation in its incidence using each set of criteria. We then compared these diagnostic criteria to our proposed new criteria and investigated cases where disagreement occurred. Results: We identified 41 cases (24%) in which at least one established criteria set classified the case as infected while at least one other criteria set classified the case as uninfected. With our proposed criteria, the infected/uninfected ratio was 92/80. The proposed criteria had a large variance in sensitivity (54%-100%), specificity (39%-100%), and accuracy (53%-100%) when using each of the established criteria sets as the reference standard. Conclusions: The discrepancy between definitions of infection complicates interpretation of the literature and the treatment of failed TKAs owing to PJI. Based on our findings, we suggest establishing a common set of diagnostic criteria utilizing aspirate analysis to improve the treatment of PJI and facilitate interpretation of the literature. Level of Evidence: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.