Schisandra fructus has been used for treatment of cough and thirst in Korea. However, its therapeutic mechanisms remain largely unclear. To investigate the biological effect of Schisandra fructus water extract (SFWE), we examined the effect of SFWE on the phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-induced pro-inflammatory cytokine secretion in the human mast cell line HMC-1. HMC-1 cells were stimulated with PMA plus A23187 in the presence or absence of SFWE. Tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF) productions were measured by enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. Inhibitory IkappaB/nuclear factor-kappaB (NF-kappaB) expression was assessed by western blot. SFWE suppressed PMA plus A23187-induced TNF-alpha, IL-6, and GM-CSF production in dose-dependent manners. Furthermore, SFWE inhibited IkappaB degradation and NF-kappaB nuclear translocation. These results suggest that SFWE inhibits the secretion of pro-inflammatory cytokines in HMC-1 cells through blockade of IkappaB degradation and NF-kappaB activation. Taken together, these findings may help elucidate the mechanism of action of this medicine in the modulation of mast cell activation in inflammatory conditions.