OBJECTIVE—We investigated the relation between soluble CD36 (sCD36), risk markers of atherosclerosis and body composition, and glucose and lipid metabolism in polycystic ovary syndrome (PCOS). RESEARCH DESIGN AND METHODS—Thirty PCOS patients were randomized to 30 mg/day pioglitazone or placebo for 16 weeks. Fourteen weight-matched healthy female subjects were included as control subjects. sCD36, oxidized LDL (oxLDL), high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, euglycemic-hyperinsulinemic clamps, and whole-body dual-energy X-ray absorptiometry scans were performed. RESULTS—sCD36 (2.87 relative units [0.88–9.36] vs. 1.67 relative units [0.72–3.89]), oxLDL (44.9 units/l [26.9–75.1] vs. 36.1 units/l [23.4–55.5]), and hsCRP (0.26 mg/dl [0.03–2.41] vs. 0.12 mg/dl [0.02–0.81]) were significantly increased in PCOS patients versus control subjects (geometric mean ± 2 SD). In PCOS, positive correlations were found between central fat mass and sCD36 (r = 0.43), hsCRP (r = 0.43), and IL-6 (r = 0.42) (all P < 0.05). After adjusting for fat mass, sCD36 and oxLDL correlated inversely with measures of insulin-stimulated glucose metabolism and positively with lipid oxidation during insulin stimulation in PCOS patients and control subjects (n = 44). sCD36 and oxLDL were significant independent predictors of glucose and lipid metabolism, whereas hsCRP and IL-6 showed no significant contribution. Following pioglitazone treatment, insulin sensitivity increased, whereas sCD36 (3.21 relative units [0.76–13.6] vs. 2.33 relative units [0.84–6.46]) and hsCRP decreased (P < 0.05). No significant changes were measured in body composition. CONCLUSIONS—sCD36 and oxLDL correlated with measures of insulin sensitivity independent of central fat mass. Pioglitazone treatment reduced sCD36 while improving insulin-stimulated glucose metabolism, further supporting the association between sCD36 and insulin resistance in PCOS.