Background: The immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis and sinusitis. The discovery of drugs for the treatment of immediate-type allergic disease is a very important subject in human health. Isodon japonicus Hara (Labiatae) (IJAE) has been used for centuries as a traditional medicine in Korea and is known to have an anti-inflammatory effect. However, its specific mechanism of action is still unknown. In this report, we investigated the effect of IJAE on the immediate-type allergic reaction and studied its possible mechanisms of action, focusing on the mast cell-mediated allergic reaction. Methods: IJAE extracts were anally administered to mice for high and fast absorption. Compound 48/80-induced mortality and compound 48/80- or immunoglobulin E (IgE)-induced histamine release were measured to evaluate the antiallergic effects of IJAE. The effect of IJAE on the model of local allergic reaction in vivo, passive cutaneous anaphylaxis (PCA), was investigated. The production of tumor necrosis factor-α (TNF-α) was measured by Western blotting. Results: IJAE inhibited compound 48/80-induced systemic reactions and plasma histamine release in mice. IJAE decreased the PCA reaction activated by anti-dinitrophenyl (DNP) IgE antibody. IJAE dose-dependently reduced histamine release from rat peritoneal mast cells activated by compound 48/80 or anti-DNP IgE. Furthermore, IJAE decreased the production of TNF-α in phorbol 12-myristate 13-acetate plus calcium ionophore A23187-stimulated human mast cells. Conclusion: Our findings provide evidence that IJAE inhibits mast cell-derived immediate-type allergic reactions, and also demonstrate the involvement of TNF-α in these effects. We propose the clinical use of IJAE in mast cell-mediated immediate-type allergic diseases.