Inappropriate repair following injury to the epithelium generates persistent activation which may contribute to airway remodeling. In the present study we hypothesized that IL-13 is a normal mediator of airway epithelial repair. Mechanical injury of confluent airway epithelial cell (AEC) monolayers induced expression and release of IL-13 in a time-dependant manner coordinate with repair. Neutralizing of IL-13 secreted from injured epithelial cells by shIL-13R2.FC significantly reduced epithelial repair. Moreover, exogenous IL-13 enhanced epithelial repair and induced Epidermal Growth Factor Receptor (EGFR) phosphorylation. We examined secretion of two EGFR ligands, EGF and HB-EGF, after mechanical injury. Our data showed a sequential release of the EGF and HB-EGF by AEC after injury. Interestingly, we found that IL-13 induces HB-EGF, but not EGF, synthesis and release from AEC. IL-13 induced EGFR phosphorylation and the IL-13 reparative effect on AEC are mediated via HB-EGF. Finally, we demonstrated that inhibition of EGFR tyrosine kinase activity by tyrphostin AG1478 increases IL-13 release after injury, suggesting negative feedback between EGFR and IL-13 during repair. Our data, for the first time, showed that IL-13 plays an important role in epithelial repair, and that its effect is mediated through the autocrine release of HB-EGF and activation of EGFR. Dysregulation of EGFR-phosphorylation may contribute to a persistent repair phenotype and chronically increased IL-13 release, and in turn result in airway remodeling.