Airway epithelial cell (AEC) proliferation is crucial to the maintenance of an intact airway surface and the preservation of host defenses. The factors that regulate AEC proliferation are not known. Keratinocyte growth factor (KGF), also known as FGF-7, is a member of the fibroblast growth factor family and a known epithelial cell mitogen. We studied the influence of KGF on the growth of cultured human bronchial epithelial cells and on bronchial cells of rats treated with KGF in vivo. First, we demonstrated the mRNA for the KGF receptor (KGFR) in both normal human bronchial epithelial (NHBE) cells and BEAS-2B cells (a human bronchial epithelial cell line). KGF caused a dose-dependent increase in DNA synthesis, as assessed by thymidine incorporation, in both cell types, with a maximal twofold increase in NHBE cells after 50 ng/ml KGF (P < 0.001). KGF also induced a doubling in NHBE cell number at 10 ng/ml (P < 0.001). Finally, we determined the effect of intratracheal administration of KGF to rats on proliferation of AEC in vivo. Measuring bromodeoxyuridine (BrdU) incorporation in AEC nuclei, KGF increased BrdU labeling of rat AEC in both large and small airways by approximately threefold compared with PBS-treated controls (P < 0.001). Thus KGF induces proliferation of bronchial epithelial cells both in vitro and in vivo.