In order to study possible interactions between opioids and cigarette smoking, we examined the effects of oral methadone administration on the smoking behavior of five male methadone-maintenance patients. Isolated subjects smoked their regular brand of cigarettes ad libitum in a naturalistic laboratory environment while reading or watching television. Ninety minutes before each daily 2-hr smoking session subjects received either placebo, dextromethorphan (a taste blind) or one of three doses of methadone, 0.5, 1.0 or 2.0 times their regular maintenance dose (40-60 mg). Each subject received each treatment five times, in a mixed order across days. Methadone pretreatment resulted in a dose-related increase in the number of cigarettes smoked per session (from a mean of 2.8 after placebo to 5.6 after the high dose of methadone). The total time spent puffing during the session increased from a mean of 27 sec after placebo to 74 sec after the high dose of methadone. CO levels in expired air (a measure of actual smoke inhalation) showed corresponding dose-related increases. Methadone administration also resulted in dose-related decreases in pupil diameter and increases in subjective ratings of smoking satisfaction and dose-strength. Dextromethorphan had no significant effects on any measure of smoking behavior or subjective response. The results demonstrate that methadone can produce substantial increases in cigarette smoking and may have implications regarding the proposed role of endogenous opioids in the smoking process.