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OBJECTIVES To determine if decreases in the Karnofsky Performance Score (KPS) while on the waitlist predict decreased survival after lung transplantation (LTx). DESIGN A retrospective evaluation of the United Network for Organ Sharing database. The KPS was evaluated at the time of listing for transplant and at the time of transplantation. Group I consisted of patients having a decrease in KPS during the time on the waiting list (from the time of listing to the time of transplant), and Group II consisted of patients whose KPS stayed the same or increased during the same period. The authors used propensity-score weighting for comparisons of these groups. SETTING Retrospective observational database review. PARTICIPANTS Adult patients undergoing lung transplantation. INTERVENTIONS None. Patients were stratified according to a change in their KPS. MEASUREMENTS AND MAIN RESULTS Patient and graft survival of patients with decreasing or not decreasing KPS were compared. Of the 27,558 subjects included in the analysis, 17,986 (65%) had worsening KPS, which was associated with worse graft (p = 0.0003) and patient (p = 0.0019) survival after LTx. Using multivariate regression, a decrease in KPS of ≥40 was associated with decreased survival, and an increase of ≥40 was associated with improved survival (HR = 1.245, 95% CI [1.181-1.312], p < 0.0001 and HR = 0.866, 95% CI [0.785, 0.955], respectively). Among patients with a KPS <40 at the time of transplant, those with a decrease in KPS of ≥40 had decreased graft and patient survival compared with those with a smaller decrease (p = 0.0002 and p = 0.0021, respectively). CONCLUSIONS Deterioration of KPS on the waiting list for LTx is associated with significantly greater postoperative mortality in patients after LTx. These results should be taken into consideration when allocating organs. Strategies to increase or to prevent a decrease in KPS before LTx should be evaluated.