Keratinocytes have histamine H₁ and H₂ receptors, but their functions are poorly understood. To clarify the role of histamine receptors in the epidermis, we examined the effects of histamine receptor antagonists and agonists applied epicutaneously on the recovery of skin barrier function disrupted by tape stripping in hairless mice. Histamine H₂ receptor antagonists famotidine and cimetidine accelerated the recovery of skin barrier function, but histamine and histamine H₂ receptor agonist dimaprit delayed the barrier repair. Application of compound 48/80, a histamine releaser, also delayed the recovery. Imidazole, an analog of histamine, had no effect. The histamine H₁ receptor antagonists diphenhydramine and tripelennamine accelerated the recovery. Histamine H₃ receptor agonist N^α-methylhistamine and antagonist thioperamide had no effect. In addition, topical application of famotidine or diphenhydramine prevented epidermal hyperplasia in mice with skin barrier disrupted by acetone treatment in a dry environment (humidity <10%) for 4 d. In conclusion, both the histamine H₁ and H₂ receptors in the epidermis are involved in skin barrier function and the cutaneous condition of epidermal hyperplasia.