In recent years, anti-allergic effects of food factors have been attracting attention as a treatment for allergic diseases with fewer side effects. Previous study demonstrated that oral administration of the polysaccharide from Pyropia yezoensis f. narawaensis (PPY) to mice improved allergic responses, and that the suppressive effect involved an increase in IL-10 secretion into the blood. However, it was not clear how IL-10 secretion was related to the anti-allergic activity of oral administration of PPY. The aim of the present study was to investigate the mechanism of anti-allergic effect of PPY. PPY inhibited allergic responses without suppressing the increase in serum IgE levels in mice model of active cutaneous anaphylaxis, suggesting that PPY suppressed allergy by affecting post-sensitization phase. PPY did not inhibit cell degranulation when RBL-2H3 cells were treated directly with IL-10 alone, but coexistence of IL-10 and hydrogen peroxide (H2O2) inhibited its degranulation. Furthermore, PPY increased H2O2 release from HT-29 cells, but pretreatment with DPI, an NADPH oxidase inhibitor, suppressed H2O2 production. Therefore, when N-acetylcysteine, a reactive oxygen species scavenger, was administered orally at the simultaneous time with PPY, the PPY-induced suppression of ear edema was eliminated. In conclusion, the results of the present study indicate that PPY exerts its anti-allergic effects through IL-10 production from intestinal epithelial cells with NADPH oxidase-mediated H2O2 production.