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Clinical stigmata of polycystic ovary syndrome include hirsutism, obesity, menstrual disturbances, and infertility. These symptoms impair health-related quality of life. Depression is also common. The relationship among depression, symptom self-perception, and quality of life in polycystic ovary syndrome is poorly understood.We sought to investigate the relationship between health-related quality of life and depression in women with polycystic ovary syndrome.We conducted a secondary analysis of a multicenter, randomized clinical trial (Pregnancy in Polycystic Ovary Syndrome II, NCT00719186) comparing clomiphene citrate vs letrozole in the treatment of infertility. Subjects included 732 women ages 18–40 years with polycystic ovary syndrome by modified Rotterdam criteria. The validated Polycystic Ovary Syndrome Health-Related Quality of Life survey was self-administered, assessing the following domains: emotions, body hair, body weight, menstrual problems, and infertility; scores range from 1–7, with lower numbers indicating poorer quality of life. Depression was evaluated via the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire. Quality-of-life scores were compared between depressed and nondepressed women. Multivariate linear regression models analyzed the association between depression and quality-of-life scores, controlling for age, body mass index, hirsutism score, and duration of infertility.In all, 64 women (8.4%) met criteria for depression. Depressed women reported reduced quality of life in all domains compared to nondepressed women: mood (3.1 vs 4.6, P < .001), body hair (3.5 vs 4.2, P = .002), weight (2.0 vs 3.5, P < .001), menstrual problems (3.3 vs 4.1, P < .001), and infertility (1.9 vs 3.0, P < .001). Global quality-of-life score was reduced in depressed women (2.8 vs 3.9, P < .001). Impairments in quality of life in depressed women persisted in all domains after controlling for objective parameters including age, body mass index, hirsutism score, and infertility duration.Depression is associated with reduced quality of life related to polycystic ovary syndrome symptoms. Disturbances in health-related quality of life in depressed women are not explained by objective measures including body mass index, hirsutism scores, and duration of infertility. Depression may color the experience of polycystic ovary syndrome symptoms and should be considered when there is significant discordance between subjective and objective measures in women with polycystic ovary syndrome.