To evaluate whether insulin resistance is associated with depression risk in women with polycystic ovary syndrome (PCOS), independent of other factors, including body mass index (BMI). Cross-sectional. Tertiary university center. A total of 301 women, aged 14-52 years, with PCOS by Rotterdam criteria, consecutively examined between 2006 and 2013. Complete history and physical examinations, including endovaginal ultrasounds, dermatologic assessments, completion of Beck Depression Inventory Fast Screen (BDI-FS), and serum testing. Scores >4 on BDI-FS indicated a positive screen for depression. Scores were further subdivided into mild (5-8), moderate (9-12), and severe (>12) depression risk. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). A total of 131 women (44%) were at risk for depression, determined by positive BDI-FS screening. These patients had higher BMI (32.3 vs. 28.5), and elevated insulin resistance, assessed by HOMA-IR (5.2 vs. 2.6), compared with patients with negative depression screening. In a stratified analysis by BMI category, obese women with positive depression screens had elevated HOMA-IR, compared with obese women with normal BDI-FS scores (7.4 vs. 4.1). In a multivariate logistic regression analysis, HOMA-IR was independently related to the odds of depression risk after controlling for age, ethnicity, BMI, and exercise (odds ratio: 1.07). Depression is common in PCOS. After controlling for confounders in multivariate regression analyses, we found HOMA-IR to be significantly associated with depression risk. Our data suggest a complex interplay among insulin resistance, obesity, and depression in PCOS, warranting additional investigation. Mental health assessment is indicated in comprehensive care of patients with PCOS.