ABSTRACT: This study aimed to evaluate the association of knee osteoarthritis (OA) with comorbidities and health-related quality of life (HRQOL).A total of 8,907 (weighted n = 13,687,058) participants aged ?50 years who had undergone knee radiography were selected from the 2010-2012 Korea National Health and Nutrition Examination Survey. OA was classified into four subgroups based on the presence or absence of pain and radiographic OA (ROA): non-OA (Pain-/ROA-), pain only (Pain+/ROA-), ROA only (Pain-/ROA+), and painful ROA (Pain+/ROA+). ROA was defined as Kellgren-Lawrence grade ? 2. HRQOL measurements including EuroQOL visual analogue scale (EQ-VAS) scores and the five dimensions and summary index of the EuroQOL-5 dimension (EQ-5D index) were also analyzed. Multivariable logistic regression and linear regression analyses were performed.After adjustment for socioeconomic and lifestyle characteristics, cardiovascular disease, malignancy, and other comorbidities were not significantly associated with OA. Pain only and painful ROA were each significantly associated with limitations in physical activity (odds ratio (OR) 2.66, 95% CI 2.07-3.44, p < 0.001 and OR 2.83, 95% CI 2.25-3.58, p < 0.001, respectively), lower EQ-VAS (?-coefficient = -10.95, p < 0.001 and ?-coefficient = -9.75, p < 0.001, respectively), and EQ-5D index (?-coefficient = -0.10, p < 0.001 and ?-coefficient = -0.13, p < 0.001) compared with the non-OA group, whereas ROA only was not associated with limitations in physical activity or lower HRQOL score.Comorbidities were not significantly associated with knee OA after adjustment. Knee OA was associated with physical activity and HRQOL. Painful knee OA, with or without ROA, was more strongly associated with decreased physical activity and lower quality of life than ROA without pain.