Background: Obesity is a very important risk factor for cardiovascular disease, type 2 diabetes mellitus, hypertension, osteoarthritis, fatty liver, metabolic syndrome and respiratory problems. Many weight-reducing drugs cannot be used in obese patients because of numerous complications. Fluoxetine, an antidepressant, and metformin, an antidiabetic drug, reduce weight as their side effect, but the potency of each drug is not always enough. Here, we studied the effects of combination therapy of them for weight reduction in obese women. Materials and methods: This study was designed as an open, prospective, controlled clinical trial. Obese and overweight patients referred to obesity clinics were first put under a diet and behavior therapy education program before being invited to this study. The patients who accepted drug therapy were put in the case group. Those who did not accept drug therapy were put in the control group. Fluoxetine, 20 mg daily, and metformin, 500 mg three times daily, were prescribed to the participants. Weight and body mass index (BMI) changes within case and control groups were analyzed by paired t-tests and between groups by t-testing. Side effects were evaluated by interview and questionnaire. Subjects: Two hundred and three patients were referred to obesity clinics. Of these, 177 were female with 91 being volunteers for this study. Of this 91, 66 were in the case group and 25 in the control group. Results: In a 6.68-month period, a 7.89 kg decrease in weight (9.32%) and a 3.43 U decrease in BMI (10.14%) were observed in participants of the case group that was statistically significant (Po0.0001). The participants of the control group were followed for a mean period of 8.12 months. In this period, the participants of the control group showed a 0.48 kg decrease in weight (0.52%) and a 0.11 U decrease in BMI (0.42%). This was not significant. No serious side effects of the drugs were observed in the case group.Conclusion: This open-label pilot study of combination therapy of metformin and fluoxetine gave encouraging weight reduction, and these results suggest the need for a randomized double-blind clinical trial comparing the two components and the combination to placebo.