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Background: Little is known about the association between different levels of physical activity (PA) and health-related quality of life (HRQoL) in the general Iranian population across sex groups. The current study aims to investigate the association between PA and HRQoL across sex groups, various types of physical activity (leisure time and occupational) and different dimensions of HRQoL in a large population of Tehranian adults.Methods: This cross-sectional study was conducted using data from the Tehran Lipid and Glucose Study (TLGS). Data was collected from 7800 adults on their PA habits and HRQoL. Information on PA and HRQoL were assessed using the Modifiable Activity Questionnaire (MAQ) and Short-Form 12-Item Health Survey version 2 (SF-12v2), respectively. Poor HRQoL was defined as the first quartile of HRQoL scores and logistic regression analysis was used to assess the association between physical activity levels and poor HRQoL.Results: The mean age of participants was 46.4 ± 14.9 years and 45.6% of them were male. Levels of PA were significantly associated with most subscales of HRQoL in both men (p < 0.05) and women (p < 0.01). In both sexes, leisure time PA was significantly correlated to all subscales of HRQoL (p < 0.05) except for bodily pain in both sexes and for social functioning and role emotional in men. In adjusted models, men with both moderate (OR: 1.55, 95%CI: 1.18-2.04; p = 0.002) and low (OR: 1.46, 95%CI: 1.11-1.91; p = 0.007) levels of PA had a significantly higher chance of reporting poor mental component summary (MCS) compared to their counterparts with high levels of PA. Furthermore, women with low levels of PA had a significantly higher chance of reporting poor physical component summary (PCS) (OR: 2.39, 95% CI: 1.63-3.49; p < 0.001) compared to those with high levels of PA.Conclusion: The findings show an association between PA and both domains of HRQoL in men and mostly the physical domain in women, suggesting a sex-specific pattern for this association, which could be considered to motivate participation in PA programs in future health promotion interventions. [ABSTRACT FROM AUTHOR]