OBJECTIVE: Obesity is frequently present in women with the polycystic ovary syndrome (PCOS) and aggravates insulin resistance (IR) and hyperandrogenemia. We aimed to assess the effects of orlistat combined with lifestyle changes in overweight and obese women with PCOS and body mass index (BMI)-matched controls.DESIGN: Prospective study.PATIENTS: We studied 101 women with PCOS (age 26·1 ± 6·4 years, BMI 34·5 ± 5·9 kg/m(2) ) and 29 BMI-matched women with normal ovulating cycles. All women were instructed to follow a low-calorie diet to exercise and were treated with orlistat 120 mg tid for 6 months.MEASUREMENTS: Metabolic and endocrine characteristics of PCOS, blood pressure (BP) and lipid profile.RESULTS: A significant and comparable reduction in BMI was observed in women with PCOS and controls. Systolic and diastolic BP decreased only in women with PCOS. Serum low-density lipoprotein cholesterol levels decreased in both women with PCOS and controls; however, this reduction was greater in controls. In contrast, serum high-density lipoprotein cholesterol levels did not change in women with PCOS and decreased in controls. Serum triglyceride levels decreased significantly and to a comparable degree in the two groups. Similarly, markers of IR improved significantly and to a comparable degree in women with PCOS and controls. Serum testosterone levels and the free androgen index decreased significantly in women with PCOS and did not change in controls.CONCLUSIONS: Orlistat combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvements in IR, hyperandrogenemia and cardiovascular risk factors.