Obesity is one of the most important health problems, which many people suffer from it. As a chronic disease, it is a precipitating factor for many medical conditions like hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, sleep apnea syndrome and some malignancies (breast, uterus, prostate and colon carcinoma). With attention to this fact that obesity is an independent risk factor associated with significant increase in morbidity and mortality, treatment of overweight individuals is very important. One of the medications for short-term weight loss is fluoxetin. In this clinical trial study, fluoxetin effect on weight loss induction during 8 weeks was investigated. 201 cases with BMI between 25-42 were selected randomly (113 female and 88 male) and all received fluoxetine (40 mg daily) for 8 weeks. Measurement was carried out after the 4th and 8th week of administration and 4 weeks after end of treatment. Management of 9 cases (4 due to weight gain and 5 due to headache) were discontinued after 4 weeks of treatment. Data assessments were performed using t-test and SPSS program. Mean body weight at first visit was 89.32 ± 13.30 kg. At the 4th, 8th week of treatment and 4 weeks after study, the mean body weight of cases reached 86.09 ± 13.27 (p=0.00), 82.69 ± 11.31 (p=0.00) and 81.97± 13.26 (p=0.00) respectively. Mean BMI at first visit was 34.90 ± 5.20kg/m2. At 4th, 8th weeks of treatment it was 33.72 ± 5.20kg/m2 and 32.40 ± 5.18 kg/m2 respectively. Mean weight loss at 4th and 8 th weeks of treatment was 3.24 kg and 6.67 kg respectively without any weight gain at the end of the 4th week after discontinuation of the drug. Fluoxetine is an effective, well-tolerated and relatively safe drug for short -term treatment of obesity.