Objective: To evaluate the efficacy of an orlistat-resveratrol (O-R) combination in subjects with obesity over a 6-month period. Methods: This study was a double-blind, parallel, randomized controlled clinical trial. Patients fulfilling the selection criteria (age from 20 to 60 years and body mass index (BMI) 30 and 39.9 kg/m 2 ) consumed an energy-reduced diet with 500 fewer calories than their usual diet for 2 weeks. Then the participants were randomly assigned to four groups, placebo, resveratrol, orlistat, or O-R, and they consumed the energy-reduced diet for 6 months. The study consisted of seven visits. During each visit, a 24-h recall was performed, along with measurements of anthropometric and serum biochemical parameters. Results: A total of 161 participants were selected. Of these, 84 participants completed the study. A significant weight loss of 26.82 kg (95% CI 28.37 to 25.26) was observed in the O-R group compared with 23.50 kg (25.05 to 21.95, P 5 0.021) in the placebo group. In contrast, the 26.02 kg (27.68 to 24.36) orlistat and 24.68 kg (26.64 to 22.71) resveratrol monotherapy losses did not significantly differ from the placebo. Significant decreases in BMI, waist circumference, fat mass, triglycerides, leptin, and leptin/ adiponectin ratio were observed with the O-R combination.