Rats were trained to discriminate the putative serotonin (5-HT) antagonist, pizotifen maleate (BC105), from saline using a two-lever drug discrimination paradigm. Pizotifen maleate (6 mg/kg, 14.6 mumol/kg, IP) or saline was administered 55 min prior to the operant training session. The pizotifen discriminative stimulus (DS) had a rapid onset (less than 7 min) and was of long duration. The pizotifen DS was dose dependent. The pizotifen DS did not generalize to the putative 5-HT antagonists, methiothepin, xylamidine, and cinanserin. Partial generalization was observed to methysergide and metergoline, and complete generalization to cyrproheptadine and the phenothiazine antihistamine, promethazine. The pizotifen DS failed to generalize to the antipsychotic chlorpromazine, the ethanolamine antihistamine diphenhydramine, the CNS stimulant, d-amphetamine, and the putative 5-HT agonists, LSD and quipazine. LSD and quipazine failed to antagonize the pizotifen DS. The results of this study suggest that different DS properties are associated with the different putative 5-HT antagonists and that pizotifen and cyproheptadine, in addition to their reported 5-HT antagonist properties, share a common property that is also associated with promethazine, probably involving antihistaminergic activity.