Background: Studying the important factors contributing to different Health-related quality of life (HRQoL) subscales is essential for implementing preventive measures to increase the HRQoL among osteoporotic patients. We here evaluated the variables affecting the mental and physical QoL in a sample population of Iranian osteoporotic women.Methods: In this cross-sectional study, the participants included 111 women with osteoporosis in 2013. Physical and mental of QoL were measured by the ECOS-16 questionnaire. Other variables included T-score, age, body mass index, educational level, marital status, duration of the disease, history of bone fracture in the past year, the number of pregnancies, and weekly walking hours. Final regression coefficients were obtained based on the total effects of estimations (decompositions of effects into direct, indirect and total effects) by SEM analysis.Results: The mean scores of physical and mental domains of QoL were 54.12±21.22 and 54.42 ±25.11 respectively. Finally, the mean of T-score was -3.21± 0.92. Based on the regression coefficients calculated in the SEM model, the number of pregnancies(-1.18), and weekly walking hours(2.19) were the main determinants of physical aspect of QoL. Furthermore, age and weekly walking hours significantly influenced the mental aspect of QoL. Conclusions: The present study indicated that weekly walking hours, the number of pregnancies, and disease duration affected physical QoL while weekly walking hours and age were predictors of mental QoL. These results can provide a guide for healthcare decision-makers to improve the life style and HRQoL of patients with osteoporosis.