Certain barriers prevent some cigarette smokers from attempting to quit, particularly the fear of post-cessation weight gain. This investigation was an open label study of naltrexone hydrochloride (25 mg/day) in combination with sustained-release (SR) bupropion hydrochloride (300 mg/day) for smoking cessation and minimization of post-quit weight gain in weight-concerned smokers. The study sample (n=20) was compared to matched controls (n=20) who received an identical psychosocial intervention and bupropion SR treatment regimen. The primary outcomes analyzed were: (a) biochemically verified continuous abstinence from smoking over the 6-week treatment, (b) point prevalence abstinence in the last 7 days of treatment, and (c) weight gain from baseline. Neither adherence to the combination pharmacotherapy nor the percentage of patients reporting adverse events differed significantly between the two groups nor were there differences in either continuous or point prevalence abstinence from smoking. Although not statistically significant in this small sample, continuously abstinent participants in the naltrexone+bupropion group gained less weight (mean=1.67 lb) than those in the bupropion only group (mean=3.17 lb; p=.35; Cohen's d=0.56). The results of this preliminary study suggest that combining naltrexone and bupropion may help minimize post-cessation weight gain, but does not result in higher smoking cessation rates compared to bupropion alone. The effect size for the difference in weight gain among continuously abstinent participants was in the moderate range, suggesting that this treatment deserves further study in an appropriately powered clinical trial as an adjunct for weight-concerned smokers, who may value the weight-suppressant effect of naltrexone.