Previous studies have shown that cotinine, a metabolite of nicotine, may antagonize some of the therapeutic effects of nicotine. The mechanisms underlying cotinine's effects are unclear, but cotinine has been observed to increase serotonin levels in the brain. Thus, it is possible that blocking serotonin effects may antagonize the actions of cotinine, thereby reducing its impact on responses to nicotine. This study determined whether granisetron, a 5HT(3) receptor antagonist, would enhance the efficacy of the nicotine patch. Subjects were randomly assigned to one of the three granisetron conditions (N=43 for 2 mg/day; N=43 for 1 mg/day; N=42 for 0 mg/day) and asked to take the assigned medication daily during 15 days of tobacco abstinence. Because we were interested in interactions between cotinine and serotonin, all groups were also treated with a 21-mg nicotine patch. Assessments of withdrawal symptoms were made for 1 week during baseline smoking and several times during the experimental period. There was a near but nonsignificant difference among groups on a measure of tobacco withdrawal and no significant differences on global measures of drug effects or physiological measures. The data do not strongly support the hypothesis that 5HT(3) agonism is the mechanism by which cotinine offsets the effects of nicotine.