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Background: Total knee arthroplasty (TKA) is an orthopedic procedure performed on patients with severe knee pain and advanced knee conditions, such as osteoarthritis and rheumatoid arthritis, in order to restore joint function. Despite the procedure's high success rates, persistent postoperative pain (PPP) remains a significant complication, affecting a substantial proportion of patients. Identifying predictors of PPP is crucial for improving patient outcomes and satisfaction. Methods: A retrospective analytic study was conducted, reviewing the medical records of patients who underwent unilateral or bilateral TKA at King Abdulaziz Medical City. The data collection focused on demographics, comorbidities, clinical presentations, surgical details, and postoperative outcomes. Data were analyzed using JMP software. A p-value of less than 0.05 was considered statistically significant. Results: This study included 838 patients, predominantly female (71.5%), with an average age of 65.4 years. Osteoarthritis was the primary reason for surgery (98.3%). The mean preoperative pain score was 3.4, and the average pain duration prior to surgery was 6.2 years. We identified dyslipidemia as a significant predictor of PPP (OR 1.40, p = 0.042), while we found younger age to be a significant predictor (OR 0.979, 95% CI 0.967–0.991, p = 0.001). Other factors such as gender, diabetes, hypertension, cardiovascular disease, anxiety disorder, mood disorder, tobacco use, chronic kidney disease, chronic lung disease, and BMI were not significant predictors of PPP. Conclusion: This study identifies younger age and dyslipidemia as significant predictors of persistent postoperative pain and improved outcomes following total knee arthroplasty Further research is needed to validate these results in diverse populations and settings, with the objective should be to refine preoperative counseling and postoperative pain management protocols. [ABSTRACT FROM AUTHOR]