Obese adults treated with the two drugs lost between 3.8 and 4.7 times more weight than a control group on the same low calorie diet and mild exercise regime.
The researchers gave a daily combination of the smoking cessation medicine bupropion and either 16mg or 32mg of opiate dependency drug naltrexone.
Over the 56 weeks of the study, the 471 participants given the stronger naltrexone dose lost 6.1% of their body-weight on average, compared with a loss of 5% for the 471 given a weaker dose and 1.3% for the 511 in the control group.
Those given a stronger dose were three times more likely to lose at least 5% of their body weight, and 48% did so.
An obesity treatment pill that combines naltrexone and bupropion is being developed by Orexigen Therapeutics which funded the study.