Severe lesions of airway epithelia are observed in cystic fibrosis (CF) patients. The regulatory mechanisms of cell migration and proliferation processes, involved in the repair of injured epithelia, then need to be better understood. A model of mechanical wounding of non-CF (NuLi) and CF (CuFi) bronchial monolayers was employed to study the repair mechanisms. We first observed that wound repair, under paracrine and autocrine epidermal growth factor (EGF) control, was slower (up to 33%) in CuFi than in NuLi. Furthermore, EGF receptor (EGFR) activation, following wounding, was lower in CuFi than in NuLi monolayers. Cell proliferation and migration assays indicated a similar rate of proliferation in both cell lines but with reduced (by 25%) CuFi cell migration. In addition, cell migration experiments performed in the presence of conditioned medium, collected from NuLi and CuFi wounded bronchial monolayers, suggested a defect in EGF/EGFR signaling in CF cells. We recently demonstrated coupling between the EGF response and K⁺ channel function, which is crucial for EGF-stimulated alveolar repair (AJP 293: L870-882, 2007). In CuFi cells, lower EGF/EGFR signaling was accompanied by a 40-70% reduction in K⁺ currents and KvLQT1, K_ATP and KCa3.1 channel expression. In addition, EGF-stimulated bronchial wound-healing, cell migration and proliferation were severely decreased by K⁺ channel inhibitors. Finally, acute CFTR inhibition failed to reduce wound-healing, EGF secretion and K⁺ channel expression in NuLi. In summary, the delay in CuFi wound-healing could be due to diminished EGFR signaling coupled with lower K⁺ channel function, which play a crucial role in bronchial repair.