Previous studies showed that diphenidol was effective on emetogens-induced pica, eating of non-nutritive substances, in rats, a model analogous to emesis in other species. We evaluated the actual antiemetic activity of diphenidol against four emetic stimuli in the dog and ferret, animals that possess an emetic reflex. In dogs, emetic responses to apomorphine were significantly prevented by diphenidol (3.2 mg/kg, i.v.), whereas diphenidol (3.2 mg/kg, i.v. x 2) showed a weak inhibition to the vomiting evoked by cisplatin. In ferrets, diphenidol (10 mg/kg, i.p.) exhibited a weak antiemetic activity on the emesis induced by copper sulfate and had no activity on emesis by loperamide. On the other hand, CP-122,721, a NK1-receptor antagonist, significantly reduced the emetic episodes to all four stimuli. These results suggest that the prediction of antiemetic activity of compounds in animals lacking an emetic reflex does not always correspond with actual antiemetic activity.