Houttuynia cordata has been used as a traditional medicine in Korea and is known to have antioxidant, anti-cancer and anti-allergic activities. The precise effect of H. cordata, however, remains unknown. In this study, we investigated the effects of H. cordata water extract (HCWE) on passive cutaneous anaphy-laxis (PCA) in mice and on IgE-mediated allergic response in rat mast RBL-2H3 cells. Oral administration of HCWE inhibited IgE-mediated systemic PCA in mice. HCWE also reduced antigen (DNP-BSA)-induced release of β-hexosaminidase, histamine, and reactive oxygen species in IgE-sensitized RBL-2H3 cells. In addition, HCWE inhibited antigen-induced IL-4 and TNF-α production and expression in IgE-sensitized RBL-2H3 cells. HCWE inhibited antigen-induced activation of NF-κB and degradation of IκB-α. To inves-tigate the inhibitory mechanism of HCWE on degranulation and cytokine production, we examined the activation of intracellular FceRI signaling molecules. HCWE suppressed antigen-induced phosphorylation of Syk, Lyn, LAT, Gab2, and PLC γ2. Further downstream, antigen-induced phosphorylation of Akt and MAP kinases (ERK1/2 and JNK1/2 but not p38 MAP kinase) were inhibited by HCWE. Taken together, the in vivo/in vitro anti-allergic effect of HCWE suggests possible therapeutic applications of this agent in inﬂammatory allergic diseases through inhibition of cytokines and multiple events of FceRI-dependent signaling cascades in mast cells.