Expression of members of the epidermal growth factor family, including epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), amphiregulin (AR), and Cripto, as well as their putative receptor, epidermal growth factor receptor (EGFR), was studied immunohistochemically in human gastric mucosa to evaluate their possible roles in cell proliferation of normal and regenerative gastric mucosa. We also examined the correlation betwen cell proliferation and EGFR by double immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and EGFR. In normal gastric mucosa, TGF-alpha, Cripto, and AR immunoreactivities were observed in the surface epithelial and parietal cells of gastric fundic glands, respectively. EGF immunoreactivity was not observed in any of normal mucosa examined. EGFR immunoreactivity was detected on foveolar cells in proliferative zones and in parietal cells. Double immunostaining revealed that EGFR immunoreactivity was distributed much more widely than PCNA immunoreactivity. PCNA positive epithelial cells adjacent to gastric ulcer margin expressed relatively intense EGFR but did not express any of the growth factors examined. On the other hand, relatively intense immunoreactivity of both TGF-alpha and Cripto was detected in PCNA-negative regenerative epithelium located distant from gastric ulcer margin. Relative immunoreactivity of AR in regenerative gastric epithelium associated with ulcer was not different from that in normal gastric mucosa. TGF-alpha, AR, and Cripto are considered to play important roles in normal gastric mucosal proliferation, and TGF-alpha and Cripto may be involved in ulcer healing, possibly via a paracrine mechanism.