Background: Gastric bypass and duodenal switch are currently performed bariatric surgical procedures. Uncontrolled studies suggest that duodenal switch induces greater weight loss than gastric bypass. Objective: To determine whether duodenal switch leads to greater weight loss and more favorable improvements in cardiovascular risk factors and quality of life than gastric bypass. Design: Randomized, parallel-group trial. (ClinicalTrials.gov registration number: NCT00327912) Setting: 2 academic medical centers (1 in Norway and 1 in Sweden). Patients: 60 participants with a body mass index (BMI) between 50 and 60 kg/m2. Intervention: Gastric bypass (n = 31) or duodenal switch (n = 29). Measurements: The primary outcome was the change in BMI after 2 years. Secondary outcomes included anthropometric measures; concentrations of blood lipids, glucose, insulin, C-reactive protein, and vitamins; and health-related quality of life and adverse events. Results: Fifty-eight of 60 participants (97%) completed the study. The mean reductions in BMI were 17.3 kg/m2 (95% CI, 15.7 to 19.0 kg/m2) after gastric bypass and 24.8 kg/m2 (CI, 23.0 to 26.5 kg/m2) after duodenal switch (mean between-group difference, 7.44 kg/m2 [CI, 5.24 to 9.64 kg/m2]; P < 0.001). Total cholesterol concentration decreased by 0.24 mmol/L (CI, −0.03 to 0.50 mmol/L) (9.27 mg/dL [CI, −1.16 to 19.3 mg/dL]) after gastric bypass and 1.07 mmol/L (CI, 0.79 to 1.35 mmol/L) (41.3 mg/dL [CI, 30.5 to 52.1 mg/dL]) after duodenal switch (mean between-group difference, 0.83 mmol/L [CI, 0.48 to 1.18 mmol/L]; 32.0 mg/dL [CI, 18.5 to 45.6 mg/dL]; P < 0.001). Reductions in low-density lipoprotein cholesterol concentration, anthropometric measures, fat mass, and fat-free mass were also greater after duodenal switch (P ≤ 0.010 for each between-group comparison). Both groups had reductions in blood pressure and mean concentrations of glucose, insulin, and C-reactive protein, with no between-group differences. The duodenal switch group, but not the gastric bypass group, had reductions in concentrations of vitamin A and 25-hydroxyvitamin D. Most Short Form-36 Health Survey dimensional scores improved in both groups, with greater improvement in 1 of 8 domains (bodily pain) after gastric bypass. From surgery until 2 years, 10 participants (32%) had adverse events after gastric bypass and 18 (62%) after duodenal switch (P = 0.021). Adverse events related to malnutrition occurred only after duodenal switch. Limitation: Clinical experience was greater with gastric bypass than with duodenal switch at the study centers. Conclusion: Duodenal switch surgery was associated with greater weight loss, greater reductions of total and low-density lipoprotein cholesterol concentrations, and more adverse events. Improvements in other cardiovascular risk factors and quality of life were similar after both procedures. Primary Funding Source: South-Eastern Norway Regional Health Authority.