OBJECTIVE To determine the frequency of Melanocortin 4 Receptor (MC4R) mutations in morbidly obese adolescents undergoing bariatric surgery and compare weight loss outcomes in patients with and without mutations. METHODS In this prospective cohort study, 135 adolescent patients evaluated for bariatric surgery were screened for MC4R mutations; 56 had 12-month postoperative data available for analysis. RESULTS MC4R mutations were detected in five of the 135 patients (3.7%); four underwent restrictive bariatric surgery. For the three patients with gastric banding, percent excess weight loss (%EWL) postoperatively was 36.0% at 5 years in one, 47% at 4 years in the second, and 85% at 1 year in the third. For the patient with gastric sleeve resection, %EWL of 96% was attained at 1 year postoperatively. The four MC4R cases had a higher, although nonsignificant, %EWL compared to 52 nonmatched controls at 12 months postoperatively (48.6% vs. 23.4%; P < 0.37). When matched by age, sex, and race to 14 controls, there was no significant difference in %EWL (P < 0.31), BMI change (P < 0.27), or absolute weight loss (P < 0.20). CONCLUSIONS The frequency of MC4R mutations is similar to prior studies, with affected patients showing beneficial weight loss outcomes.