Olanzapine (OLAN), an atypical antipsychotic medication with mixed 5-HT2/DA antagonist properties, was predicted to dose-dependently decrease urge to smoke, withdrawal, and cigarette reinforcement in smokers without psychosis. A double-blind placebo-controlled within-subjects cross-over trial investigated the acute effects of OLAN (0, 2.5, and 5.0 mg; counterbalanced order) in 24 community smokers who underwent 10-hr smoking deprivation. Urge to smoke, tobacco withdrawal, and cigarette reinforcement were assessed with cue reactivity and behavioral choice procedures. OLAN (2.5 mg) reduced withdrawal symptoms before and during cue exposure and decreased urge associated with anticipated positive affect from smoking before and during cue exposure; 5.0 mg OLAN decreased withdrawal only when cues were included. OLAN did not affect preference for cigarette puffs versus money, smoke intake, or urge to smoke associated with negative affect relief. The results indicate a potentially beneficial effect of 2.5 mg OLAN on tobacco withdrawal and urge to smoke. Combined 5HT/DA antagonists should be considered for future development of pharmacotherapies for smoking cessation.