OBJECTIVES Amfepramone is an anorectic drug used for the short-term treatment of obesity; however, its efficacy and safety in the long-term has been scarcely studied. To determine the efficacy and safety of long-acting amfepramone treatment in Mexican adult obese patients by a double blind, randomized and placebo-controlled clinical trial study  METHODS One hundred and fifty six volunteers with a body mass index (BMI) greater than 30 kg/m and less than 45 kg/m were randomized to receive a tablet of 75 mg amfepramone or placebo daily during 6 months. Primary outcomes were the absolute body weight loss and the percentage of patients who achieved at least 5% or 10% weight loss at 3 and 6 months, whereas secondary outcomes were the improvement of anthropometric and metabolic parameters. RESULTS Amfepramone treatment showed a superior efficacy to decrease the body weight than placebo at 3 (-4.9 ± 0.25 versus 0.7 ± 0.32 Kg) and 6 (7.7 ± 0.52 versus 1.1 ± 0.7 Kg) months. In addition, Sixty-four and thirty-four patients achieved at least 5% or 10% weight loss, respectively, with amfepramone at 6 months, compared with eight and zero patients of placebo. Amfepramone also improved BMI and waist circumference, but not waist-hip index (WHI), glucose, total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL) and triglycerides at 3 and 6 months. Amfepramone produced only mild adverse events and they were presented in a greater number than placebo only at 3 months, being the main adverse event dry mouth.   CONCLUSIONS Data suggest that amfepramone is effective and well tolerated in the long-term treatment of Mexican obese patients.