PURPOSE. To investigate the role played by epiregulin in corneal epithelial wound healing in vivo in epiregulin-knockout (KO) mice and cultured mouse corneal epithelial cells (MCECs). METHODS. A 2 mm diameter central epithelial wound was created in epiregulin-KO and wild-type (WT) mouse corneas. The size of the unhealed area and epithelial cell proliferation and migration were examined. Myeloperoxidase assay was performed to determine the number of PMN cells infiltrating into the corneal stroma. Real-time polymerase chain reaction was used to determine the expression of the mRNA of inflammatory cytokines in the corneal epithelial cells. The expression of chemokine (C-X-C motif) ligand (CXCL)2 response to interleukin (IL)-1 was examined in MCECs with or without recombinant mouse epiregulin. Repetitive injuries were made to determine the effect of inflammation in healing in epiregulin-KO mice. RESULT. After a single injury, the corneal epithelial wound healing and cell migration and proliferation were unimpaired. However, corneal opacities and a larger number of infiltrating PMN cells were observed in epiregulin-KO mice. The expressions of IL-1 IL-6, CXCL1, and CXCL2, were higher in epiregulin-KO than in WT corneal epithelia cells. The addition of epiregulin significantly reduced the response in the expression of CXCL2 to IL-1 in MCECs. For repetitive injuries, a significant delay of healing and more severe opacities were observed in epiregulin-KO mice than in WT mice. CONCLUSION. Our results indicate that during wound healing, epiregulin may regulate the expression of cytokines and chemokines to reduce an excessive accumulation of PMN cells which will cause corneal opacity and persistent epithelial defects.