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Total knee replacement is a highly successful and frequently performed operation. Technical outcomes of surgery are excellent, with favorable early postoperative health-related quality of life. This study reviews intermediate and long-term quality of life after surgery.A systematic review and meta-analysis of all studies published from January 2000 onward was performed to evaluate health-related quality of life after primary total knee replacement for osteoarthritis in patients with at least three years of follow-up. Key outcomes were postoperative quality of life, function, and satisfaction compared with the preoperative status. Strict inclusion and exclusion criteria were applied. Quality appraisal and data tabulation were performed with use of predefined criteria. Data were synthesized by narrative review and random-effects meta-analysis utilizing standardized mean differences. Heterogeneity was assessed with the tau2 and I2 statistics.Nineteen studies were included in the review. Intermediate and long-term postoperative quality of life was superior to the preoperative level in qualitative and quantitative analyses. The pooled effect in combined WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) and KSS (Knee Society Score) outcomes was a marked improvement from baseline with respect to the total score (2.17; 95% CI [confidence interval], 1.13 to 3.22; p < 0.0001) and the pain (1.72; 95% CI, 0.97 to 2.46; p < 0.00001) and function (1.26; 95% CI, 0.87 to 1.64; p < 0.00001) domains. Most patients were satisfied with the surgery and derived substantial benefits for daily functional activities. Tau2 (0.20 to 1.10) and I2 (90% to 98%) values implied significant clinical and statistical heterogeneity.Total knee replacement confers significant intermediate and long-term benefits with respect to both disease-specific and generic health-related quality of life, especially pain and function, leading to positive patient satisfaction. Recommendations for necessary future studies are provided.Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.