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Background and Purpose: Few studies have examined the impact of comorbidity on functional and clinical knee scores after primary total knee arthroplasty (TKA). We compared the effect of having a high Charlson Comorbidity Index (CCI), relative to a low CCI, on changes in the American Knee Society Score (AKSS) functional and clinical scores from baseline to week 52 after TKA in patients with knee osteoarthritis (OA)., Methods: This population-based cohort study included 22,533 patients identified in the Danish Knee Arthroplasty Register from 1997 to 2021. Patients were classified as having low, medium, or high comorbidity based on CCI. The outcome was defined as the mean change (from preoperative to 1-year post-TKA) in functional and clinical knee scores measured by the AKSS (0-100). The association was analyzed using multiple linear regression by calculating mean change scores adjusting for sex, age, weight, cohabiting status, and baseline AKSS., Results: The prevalence of patients with low, medium, and high comorbidity was 75%, 21%, and 4%, respectively. The mean change score in functional AKSS for patients with high comorbidity was -6 points (95% confidence interval [CI] -7 to -5) compared with low comorbidity. The mean change score in clinical AKSS for patients with high comorbidity was -1 point (CI -2 to 0) compared with low comorbidity., Conclusion: Patients with knee OA and medium or high comorbidity can expect similar improvements in functional and clinical AKSS after TKA to patients with low comorbidity.