The effect of fluoxetine hydrochloride, a 5-HT uptake inhibitor (60 mg/day PO), in preventing weight gain associated with nicotine reduction was investigated in participants in a double-blind, placebo-controlled smoking-cessation trial. A lunch of cheese pizza and chocolate bars was offered, and caloric intake was monitored. The analysis focused on subjects (placebo: n = 11; fluoxetine: n = 10) who succeeded in reaching cotinine levels of less than 50% of their starting cotinine levels (signifying a stringent reduction in nicotine intake) and who participated in pre- and post-nicotine reduction lunch sessions 70 days apart. Subjects on placebo gained significantly more weight (mean +/- SEM = +3.3 +/- 0.7 kg) than subjects on fluoxetine (-0.6 +/- 1.2 kg). In fluoxetine-treated subjects, weight gain/loss was strongly correlated with initial body mass index, with higher BMI being associated with greater decreases in weight. A trend towards decreased caloric intake in the fluoxetine group was observed; the change in total calories at lunch was significantly correlated with weight change, an association accounted for principally by change in pizza intake. We conclude that fluoxetine treatment effectively prevents the weight gain that accompanies nicotine reduction and that this phenomenon is mediated, at least in part, by diminished caloric intake.