Prostaglandin E₂ regulates the colonic inflammation via PGE receptor EP4. EP4 facilitates wound healing through lymphangiogenesis. In this study, we examined whether EP4 is involved in the resolution of acute colitis by enhancement of inflammation-associated lymphangiogenesis. Experimental colitis was induced by administration of 2% DSS into C57BL/6 mice. DSS in drinking water was supplied for 7 days, followed by replacement of more 7 days-tap water. Mice were orally given EP4 antagonist (ONO-AE3-208; ONO) or vehicle for 7 days throughout the water-supply period. Compared with vehicle-treated mice, ONO-treated mice displayed increases in weight loss and clinical signs of colitis, and decreases in colon length. ONO increased lymphatic vessel density, which was associated with enhancement of lymphatic markers including LYVE-1 and VEGFR3. Pro-lymphatic vessel growth factors also were elevated. Extensive infiltration of macrophages into the colonic tissues was found, which was accompanied with up-regulated expression of TNFα and iNOS, and down-regulated expression of TGFβ. These results suggest that EP4 signaling promotes healing of DSS-induced colitis through attenuation of macrophage infiltration and lymphangiogenesis.