Importance: Medical treatment options for pediatric obesity remain limited. Glucagon-like peptide-1 (GLP-1) receptor agonists induce weight loss by suppressing appetite and increasing satiety, but few studies have evaluated this therapy as a treatment for obesity. Objective: To evaluate the effects of exenatide on body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and cardiometabolic risk factors in adolescents with severe obesity. Design: Three-month, randomized, double-blind, placebocontrolled, multicenter clinical trial followed by a 3-month open-label extension. Setting: An academic medical center and an outpatient pediatric endocrinology clinic. Patients: A total of 26 adolescents (12-19 years of age) with severe obesity (BMI≥1.2 times the 95th percentile or BMI≥35). Intervention: All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. Main Outcome Measures: The primary end point was the mean percent change in BMI measured at baseline and 3 months. Secondary end points included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A1c, fasting glucose, fasting insulin, and lipids at 3 months. Results: Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared with placebo (-2.70% [95% CI,-5.02% to -0.37%]; P=.03). Similar findings were observed for absolute change in BMI (-1.13 [95% CI,-2.03 to-0.24]; P=.02) and body weight (-3.26 kg [95% CI, -5.87 to -0.66 kg]; P=.02). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the openlabel extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). Conclusions and Relevance: These results provide preliminary evidence supporting the feasibility, safety, and efficacy of GLP-1 receptor agonist therapy for the treatment of severe obesity in adolescents.