The effects of histamine H₁ receptor antagonists on compound 48/80-induced scratching behavior were studied in mice. Classical histamine H₁ receptor antagonists such as diphenhydramine and chlorpheniramine caused a potent depressant effect on compound 48/80-induced scratching behavior. Histamine H₁ receptor antagonists having antiallergic activity (an inhibition of mast cell degranulation), such as azelastine and oxatomide and nonsedative histamine H₁ receptor antagonists such as terfenadine, epinastine and astemizole, also showed a relatively potent effect. On the other hand, the effects of tranilast and cromolyn sodium—antiallergic drugs without histamine H₁ receptor antagonistic activity—were extremely weak. Diazepam had weak or no depressant effects on compound 48/80-induced scratching behavior. These results suggest that inhibition of compound 48/80-induced scratching behavior is mainly due to histamine H₁ receptor antagonistic activity and not to the sedative action of the drugs.