It has been previously reported (M. Yashiro et al., Jpn. J. Cancer Res., 84: 883–886, 1994) that a growth factor secreted by human gastric fibroblasts stimulated proliferation of human scirrhous gastric carcinoma cells in vitro, suggesting a similar paracrine action in the gastric submucosa. The present study established the identity of the growth factor as keratinocyte growth factor (KGF). Increase in numbers and incorporation of [³H]thymidine in scirrhous gastric carcinoma cell lines (OCUM-2M and OCUM-11) in response to culture medium from a gastric fibroblast line (NF-8 and NF-21) were duplicated by substitution of KGF and inhibited by addition of anti-KGF antibody. Effects were specific for scirrhous carcinoma cells in distinction to well-differentiated gastric carcinoma cell lines. Fibroblasts, especially gastric fibroblasts, expressed KGF mRNA, whereas gastric cancer cells did not. Conversely, scirrhous gastric cancer cells expressed more KGF receptor mRNA than well-differentiated gastric adenocarcinoma cell, whereas gastric fibroblasts did not express this mRNA. ELISA detected high concentrations of KGF in medium from gastric fibroblasts, much lower concentration in medium from other fibroblasts, and no KGF in medium from gastric cancer cells. Western analysis indicated that KGF in gastric fibroblasts lysates had a molecular weight of M_r 19,000, within the range suggested in our previous report. Thus, gastric fibroblasts secretion of KGF is likely to underline the remarkable proliferation of scirrhous gastric cancer cells in a paracrine manner.