Understanding the factors that contribute to health-related quality of life (HRQOL) is critical for developing the most appropriate interventions for improving or maintaining the HRQOL in polycystic ovary syndrome (PCOS) patients. This study sought to determine the most significant predictors of the HRQOL in patients with PCOS. This was a cross-sectional study of 300 women with PCOS that was carried out in Kashan, Iran. A sample of women with PCOS was entered into the study and completed the following questionnaires: the Hospital Anxiety and Depression Scale, the Body Image Concern Inventory (BICI), the Rosenberg's Self-Esteem Scale score, the modified polycystic ovary syndrome health-related quality of life questionnaire, the Female Sexual Function Index. Both direct and indirect relationships among clinical severity, psychological status, self-esteem, body image, and sexual function as independent predictors of HRQOL were examined using structural equation modeling (SEM) analysis. By using the SEM, we simultaneously test a number of possible hypotheses concerning the interrelations among the predictors of HRQOL in PCOS patients. In relation with severity of PCOS, reproductive history and menstrual status explained a high proportion of the variance of clinical variables (factor loading 0.37 and 0.34, respectively). The highest effect on HRQL was exerted by indirect effect of clinical factor (β = 0.90), self-esteem (β = 1.12), body image (β = 1.06), and sexual function (β = 0.26) that influenced negatively HRQOL. The infertility and menstrual domains were the most affected areas of HRQOL. In relation with sexual dysfunction, the most affected domains were desire and arousal. The highest effect of PCOS symptoms on HRQOL impairment among patients was exerted by self-esteem, body image, and sexual dysfunction. With regard to HRQOL in clinical routine, we conclude these mediating factors should be taken into consideration and adequately treated if present.