In the present study, we investigated the effect of the water extract of Perilla frutescens var. acuta (Labiatae; WEPF) on the mast cell-mediated allergic reactions. WEPF was anally administered to mice for high and fast absorption. WEPF inhibited compound 48/80-induced systemic allergic reaction. WEPF attenuated immunoglobulin E (IgE)-mediated local allergic reaction. In addition, WEPF decreased the gene expression of pro-inflammatory cytokines in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated HMC-1 cells. These results indicate that WEPF inhibits mast cell-mediated allergic reactions in vivo and in vitro.