Epiregulin, a growth factor of the epidermal growth factor (EGF) family, was recently purified from conditioned medium of a mouse fibroblast-derived tumor cell line. It was reported that epiregulin exhibited bifunctional properties in the regulation of cell growth. However, the effect of epiregulin on gastric cell proliferation is not known. The aims of this study were to determine whether: (1) epiregulin affects proliferation of rabbit cultured gastric cells, (2) epiregulin-induced stimulation of cell proliferation is mediated by the tyrosine kinase pathway, and (3) epiregulin stimulates autophosphorylation of EGF-receptors. Epiregulin stimulated cell proliferation to a significant extent. This effect was completely blocked by treatment with genistein. Epiregulin stimulated tyrosine phosphorylation of a 170 kDa protein, which represents the EGF receptor, in a dose-dependent fashion. These findings suggest that epiregulin has mitogenic effects on rabbit gastric cultured cells, possibly mediated via the tyrosine kinase pathway through autophosphorylation of EGF receptors.