We examined the effects of thioperamide and (R)-alpha-methylhistamine, a histamine H3-receptor antagonist and an agonist, respectively, on a scopolamine-induced learning deficit using an elevated plus-maze test in mice. Thioperamide alone slightly improved the learning deficit induced by scopolamine, and pretreatment with zolantidine, a histamine H2-receptor antagonist, significantly enhanced the effect of thioperamide in this test. (R)-alpha-Methylhistamine, pyrilamine, ketotifen, terfenadine, and zolantidine alone at the doses tested had no effect. Moreover, the improvement by thioperamide plus zolantidine was antagonized by pretreatment with histamine H1-receptor antagonists such as pyrilamine or ketotifen, but not by terfenadine. Thus, thioperamide improved the scopolamine-induced learning deficit through central histamine H1 receptors in mice. The present results supported the hypothesis that histamine may play an important role in learning and memory.