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 the present study, we attempted to clarify the expression and role of KGFR in human colorectal cancer. The KGFR protein was detected in several colorectal cancer cell lines. Immuno-histochemically, KGFR was expressed on the luminal surface of epithelial cells in normal colorectal tissues. KGFR was expressed in 35 of 56 (62.5%) colorectal cancer patients and localized at the center of the cancer nests. Cytokeratin 20 (CK 20) colocalized with KGFR. In contrast, Ki-67 localized at the periphery of the cancer nests. Clinicopathologically, a high level of KGFR expression was associated with well-differentiated histological type (p<0.0001) and shallow wall invasion (p<0.0174). These findings indicate that KGFR may play important roles in the differentiation of normal colorectal epithelial cells and establishment of the well-differentiated histological type of colorectal cancer cells.