Objective Oral contraceptives alone or in combination with antiandrogens are commonly used in the treatment for polycystic ovary syndrome (PCOS). We aimed to determine the effects of ethinyl estradiol/drospirenone (EE-DRSP) plus spironolactone therapy on inflammation and cardiometabolic risk in PCOS. Design Prospective cohort study. Patients Twenty-three lean, normal glucose-tolerant patients with PCOS and 23 age- and body mass index (BMI)-matched healthy control women. Measurements Androgens, high-sensitivity C-reactive protein (hsCRP), homocysteine, lipids, fasting insulin, and glucose levels during a standard 75-g, 2-h oral glucose tolerance test were measured. Patients with PCOS were evaluated before and after receiving EE-DRSP (3 mg/30 mu g) plus spironolactone (100 mg/day) for 6 months. Healthy controls were evaluated at baseline only. Results hsCRP, homocysteine, lipids, insulin and glucose levels were similar between patient and control groups at baseline. EE-DRSP plus spironolactone increased hsCRP and homocysteine levels in patients with PCOS (0.50 +/- 0.28 vs 1.5 +/- 1.3 mg/l, P < 0.05 and 13.1 +/- 5.2 vs 17.6 +/- 5.3 mu m, P < 0.05, respectively). BMI, waist-to-hip ratio, LDL, HDL cholesterol and triglycerides, and glucose tolerance did not change. Modified FerrimanGallwey hirsutism scores, testosterone levels and free androgen index improved (9.1 +/- 4.2 vs 6.2 +/- 3.4, P = 0.001; 80.6 +/- 31.1 47.8 +/- 20.3 ng/dl, P < 0.05; and 10.5 +/- 7.4 vs 1.1 +/- 0.8, P < 0.001, respectively). Conclusions EE-DRSP plus spironolactone therapy in 6 months improves androgen excess in lean PCOS women without any adverse effects on adiposity, glucose tolerance status or lipid profile. However, this combination increases hsCRP and homocysteine levels.