We examined the effects of oral caffeine on cigarette smoking and subjective response in a group of six smokers who smoked cigarettes ad libitum in a naturalistic laboratory environment. A within-subject, repeated-measures design was used, and each subject received placebo, caffeine base (50 to 800 mg), or d-amphetamine sulfate (25 mg) on several occasions before 90-min daily smoking sessions. There was no evidence of an increase in the number of cigarettes smoked or the amount of smoke inhaled per session after caffeine. Caffeine increased salivary caffeine concentrations, arm tremor, and self-reported measures of mood and subjective response. The major subjective effects of caffeine were increases in tension-anxiety and dysphoric-somatic effects. In contrast, d-amphetamine induced increases in the number of cigarettes smoked and in the amount of smoke inhaled per session. The major subjective effects of 25 mg of d-amphetamine were increases in measures of well-being, euphoria, and mental efficiency. Results demonstrate that caffeine and d-amphetamine have different effects on cigarette-smoking behavior as well as on subjective response and suggest that the positive correlation between cigarette smoking and coffee drinking is not the result of a simple pharmacologic effect of caffeine.