The aim of this report was to determine the effect of fluoxetine on weight loss in a group of non depressed overweight subjects. The study was conducted for 12 weeks, and the patients were randomized for a double-blind, placebo controlled trial in the outpatient clinic of the University Hospital. Twenty patients (20-50 years old) were eligible because of BMI over 30 kg/m2, and free of other diseases including hypertension, diabetes mellitus or history of substance abuse. All patients were instructed to follow a standard hypocaloric diet, and to exercise regularly; they received either placebo or fluoxetine (20 mg twice daily after breakfast and lunch). A biochemical profile was obtained from all patients and repeated at 60 and 90 days. Fluoxetine-treated subjects (n = 10) lost weight than placebo treated subjects (n=8)(8.2 ñ 2.8 vs. 1.7ñ 1.3kg, p < 0.01) at 90 days of the trial. Also the body mass index (BMI) was significantly reduced in the fluoxetine treated group (35.1 ñ 5.1 to 31.7 ñ 5.2 kg/m2) but not in the placebo group. During active treatment, there was no significant changes in the serum biochemical profile in both groups. Side effects were minimal and similar in both groups. These results suggest that fluoxetine may be of benefit in the treatment of obese patients in whom standard dietary counseling has failed to produce weight loss.