To determine the efficacy of dexfenfluramine in the treatment of obesity and associated metabolic abnormalities, 24 premenopausal obese women given a hypocaloric diet-plus-dexfenfluramine 30 mg daily (Group A) and 20 obese women given only hypocaloric diet (Group B) for 12 months were compared. Both groups were homogeneous with regard to age, body mass index and waist to hip ratio. In addition, to investigate whether dexfenfluramine modifies insulin sensitivity independently of weight loss, group A received only dexfenfluramine and group B only placebo (single blind) for 15 days before the initiation of the diet, and insulin sensitivity was measured by insulin tolerance test before and after this period. After the first 15 days, insulin resistance was reduced significantly (p<0.01) in group A, whereas it did not change in group B. In group A, weight loss was continued to the 8th month and weight regain was not observed until the end of the study. In group B, weight loss was continued to the 4th month but weight regain was occurred between the 6-12 months. After 12 months, initial body weight was decreased by 14.7 percent (p<0.001) in group A and by 2.2 percent (p<0.01) in group B; the resultant difference between the average body weights of the groups was significant (p<0.001). After 12 months, insulin resistance, serum levels of fasting insulin, total cholesterol, triglycerides, LDL-cholesterol, uric acid, free testosterone and the areas under the curve (AUC) for serum glucose and insulin during OGTT were decreased significantly, whereas serum levels of HDL-cholesterol and dehydroepiandrosterone sulfate were increased in group A, but none of them were changed in group B. These results show that dexfenfluramine reduces body weight and associated metabolic abnormalities by contributing to the adaptation to a hypocaloric diet and, improves sex hormones profile and, decreases insulin resistance independently of weight loss in obese subjects.