OBJECTIVE: To assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs. RESEARCH DESIGN AND METHODS: This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids. RESULTS: In the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m(2), and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (-5.0 vs. -1.8%; P < 0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (-0.6 vs. -0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia. CONCLUSIONS: NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.