Objective: To test the hypothesis that increasing DHEAS levels is associated with improved insulin resistance in patients with polycystic ovary syndrome (PCOS). Design: Cross-sectional cohort analysis. Setting: Academic medical center. Patient(s): Three hundred fifty-two women with PCOS. Intervention(s): Patients presenting for evaluation of symptoms related to androgen excess were evaluated physically and biochemically through laboratory analysis. Main Outcome Measure(s): Circulating DHEAS, total T, free T, sex hormone-binding globulin (SHBG), and 17-hydroxyprogesterone (17-OHP) levels, and calculated homeostasis model assessment of insulin resistance (HOMA-IR). Result(s): Bivariate analysis indicated that all parameters were associated with HOMA-IR, except 17-OHP and age, and confirmed a negative correlation between DHEAS and HOMA-IR. Multivariate analysis indicated that increases in DHEAS, SHBG, 17-OHP, and age were associated with decreasing HOMA-IR, whereas increases in free T, body mass index (BMI), and waist-to-hip ratio (WHR) were associated with increasing HOMA-IR. In decreasing order of importance, the following variables predicted insulin resistance: BMI > WHR > age > DHEAS > free T > SHBG > 17-OHP. Conclusion(s): DHEAS is negatively correlated to insulin resistance in patients with PCOS, and in our model ranked just behind other well-established predictors including BMI, WHR, and age. Whether this is due to a direct beneficial effect on insulin action by adrenal androgens such as DHEA, or whether DHEAS simply reflects the circulating levels of hyperinsulinemia, remains to be determined. © 2009 American Society for Reproductive Medicine.