Endogenous opioid peptides have been implicated in the reinforcement of smoking and opioid antagonists have been examined to determine their role in smoking behavior. To date, the relationship between smoking behavior and chronic opiate antagonist administration during ad libitum smoking has not been investigated. The purpose of this study was to examine the relationships between naltrexone, an opiate antagonist administered orally, and smoking behavior and mood states during ad libitum smoking. A repeated measures experimental design was used. Normal adult male and female volunteers, admitted to the Clinical Research Center, were randomly assigned to naltrexone-treated (n = 22) or placebo-control (n = 21) groups in a double-blind manner. Day 1 was considered acclimation to the unit and day 2 was baseline, or pre-drug administration. On days 3, 4, and 5, subjects received 50 mg naltrexone or a placebo at 0700 and 1600 hours. Plasma nicotine and expired air carbon monoxide levels were measured daily at 1900 hours. Number of cigarettes smoked, mood states, withdrawal symptomatology and self-reported satisfaction with smoking were also quantified daily. Results indicated that plasma nicotine levels (P = 0.005), number of cigarettes smoked daily (P = 0.003) and self-reported satisfaction with smoking (P = 0.043) were significantly lower among those treated with naltrexone, compared to the placebo-control group. Expired air carbon monoxide levels did not differ between the two groups. In addition, mood states and withdrawal symptoms did not differ between groups. These findings suggest that endogenous opioid peptides influence specific smoking behavior variables.