This 56-week, randomized, placebo-controlled trial examined the efficacy and safety of naltrexone plus bupropion as an adjunct to intensive behavior modification (BMOD). A total of 793 participants (BMI = 36.5±4.2kg/m 2) was randomly assigned in a 1:3 ratio to: (i) placebo BMOD (N = 202); or (ii) naltrexone sustained-release (SR, 32mg/day), combined with bupropion SR (360mg/day) plus BMOD (i.e., NB32 BMOD; N = 591). Both groups were prescribed an energy-reduced diet and 28 group BMOD sessions. Co-primary end points were percentage change in weight and the proportion of participants who lost 5% weight at week 56. Efficacy analyses were performed on a modified intent-to-treat population (ITT; i.e., participants with 1 postbaseline weight while taking study drug (placebo BMOD, N = 193; NB32 BMOD, N = 482)). Missing data were replaced with the last observation obtained on study drug. At week 56, weight loss was 5.1±0.6% with placebo BMOD vs. 9.3±0.4% with NB32 BMOD (P<0.001). A completers analysis revealed weight losses of 7.3±0.9% (N = 106) vs. 11.5±0.6% (N = 301), respectively (P<0.001). A third analysis, which included all randomized participants, yielded losses of 4.9±0.6 vs. 7.8±0.4%, respectively (P<0.001). Significantly more NB32 BMOD- vs. placebo BMOD-treated participants lost 5 and 10% of initial weight, and the former had significantly greater improvements in markers of cardiometabolic disease risk. NB32 BMOD was generally well tolerated, although associated with more reports of nausea than placebo BMOD. The present findings support the efficacy of combined naltrexone/bupropion therapy as an adjunct to intensive BMOD for obesity. © 2010 The Obesity Society.