Aims. To evaluate the efficacy and safety of orally administered naltrexone, alone or in combination with nicotine patches, as a treatment for cigarette smoking. Design. Randomized, partially-blinded, 2 2 factorial trial using naltrexone (active vs. placebo) and nicotine patches (active vs. none). Participants. One hundred cigarette smokers. Intervention. Twelve weeks of either placebo-only, naltrexone-only, placebo with nicotine patches or naltrexone with nicotine patches. The naltrexone dose was 50 mg taken once daily, and the nicotine patch dose was 21 mg/24-hour for the first 8 weeks and 14 mg/24-hour for the remaining 4 weeks. Brief behavioral intervention was provided at each visit. Measurements. One-week pointprevalence smoking abstinence rates confirmed by an expired air carbon monoxide level of 8 parts per million (ppm) or less, daily cigarette smoking and cigarette craving. Findings. At the end of treatment, there was no effect of naltrexone on smoking abstinence. The smoking abstinence rates were 19% and 22% for the placebo only and naltrexone only treatment groups, respectively, and 48% and 46% for the placebo with nicotine patch and naltrexone with nicotine patch groups, respectively. However, the effect of the nicotine patch at this time was significant (p=0.006), but not at the 6-month follow-up. No significant effect of naltrexone was observed on daily cigarette smoking or cigarette craving during the study. Conclusions. The opioid antagonist naltrexone was not found to be effective for smoking cessation and had no significant effect on daily cigarette consumption or craving. The results of the present study provide no support for the use of naltrexone, alone or in combination with nicotine patches, as a therapeutic treatment for smoking cessation.