The keratinocyte growth factor receptor, also known as KGFR/FGFR2 IIIb, is mainly localized in epithelial cells, and participates in the proliferation of these cells. In contrast, a recent study has revealed that the overexpression of KGFR in salivary adenocarcinoma induces growth inhibition, cell differentiation and apoptosis. We attempted to clarify the expression and role of KGFR in normal and cancerous human gastric tissues and cancer cell lines. Reverse-transcription polymerase chain reaction and Western blot analyses showed KGFR mRNA and its protein expression in NUGC-4, KATO-III and MKN-7 gastric cancer cell lines, but not in the NS-8 cell line. Immunohistochemically, KGFR immunoreactivity was weakly detected in the luminal surface of normal gastric epithelial cells. In addition, KGFR immunoreactivity was strongly detected in the nucleus and cytoplasm of many parietal cells. In gastric cancer tissue, KGFR was expressed in the cell membrane and cytoplasm of cancer cells in 46 of 126 (36.5%) cases. KGFR expression in gastric cancer cells was significantly associated with early-type macroscopic findings, shallow invasion of the gastric wall and expansive growth type. KGFR expression tended to correlate with a good prognosis in gastric cancer. These findings indicate that KGFR expression plays important roles in the differentiation of normal gastric epithelial cells and parietal cell functions. Furthermore, a decreased expression level or the non-expression of KGFR in gastric cancer cells may be associated with the proliferation and invasion of gastric cancer cells and a poor prognosis for the patient.