The pharmacological consequences of combining a histamine H₁ receptor antagonist with a H₃ antagonist on cutaneous microvascular permeability due to intradermal (i.d.) injections of compound 48/80, a mast cell liberator of histamine, was studied in the anesthetized guinea pig. Compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) induced permeability responses were attenuated, as determined by Evans blue extravasation, in animals pretreated with the H₁ antagonist, chlorpheniramine (CTM; 1.0 mg/kg, i.v.) by 17 ± 4, 31 ± 4, 32 ± 4 and 37 ± 4%, respectively. Combination treatment with an H₁ and H₃ antagonist displayed greater inhibitory efficacy against the effects elicited by compound 48/80. Specifically, combined treatment with CTM (1.0 mg/kg, i.v.) and the H₃ antagonist, thioperamide (THIO 1.0 mg/kg,i.v.) inhibited the skin responses of i.d. compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) by 36 ± 4, 45 ± 4, 49 ± 4 and 54 ± 4%. A second H₃ antagonist, clobenpropit (CLOB; 0.3 mg/kg, i.v.) plus CTM (1.0 mg/kg, i.v.) also inhibited Evans blue extravasation. Treatment with THIO (1.0 mg/kg, i.v.) and CLOB (0.3 mg/kg, i.v.) administered alone had no effect on compound 48/80-induced skin responses. We conclude that combination administration of a H₁ and a H₃ histamine receptor antagonist produces greater inhibitory effect on cutaneous microvascular permeability produced by released mast cell-derived histamine than either a H₁ or H₃ antagonist administered separately. In addition, the antiallergy activity of combining a H₁ antihistamine with a H₃ antagonist activity might provide a novel approach for the treatment of allergic skin diseases such as urticaria.