A 79-year-old man in a cancer-prone family developed disseminated seborrheic keratoses over his trunk and extremities over a few decades without rapid increase. His son, mother, and one of his brothers, who died of gastric cancer, also had numerous seborrheic keratoses for a long time. He had a biliary tract cancer. Histologic examination showed hyperproliferation of basaloid cells branching downwards, as if induced by surrounding stroma. No decrease of the number of seborrheic keratoses after surgical operation has been observed. Examination for the localization of epidermal growth factor receptor (EGF-R) and HER-2/neu oncoprotein by immunohistochemistry revealed positive staining on the epithelial strands branching downwards on the specimens of seborrheic keratoses. A different pattern of expression was demonstrated in normal seborrheic keratosis. These findings suggest that some unidentified growth factors may be involved in the induction of visceral and/or cutaneous neoplasms in this family.