The neu gene (also called NGL, erbB-2, and HER-2) encodes a 185-190 kDa transmembrane glycoprotein, p185neu, which has tyrosine-specific kinase activity and is homologous to but distinct from the epidermal growth factor receptor. The normal expression of neu mRNA and protein has been demonstrated in epithelial tissues of adult animals. Also, activation of the neu oncogene has been implicated in a variety of human adenocarcinomas. In the present study, we examined the expression of the p185neu protein in normal and transformed digestive tract tissues and in a panel of digestive tract-derived cell lines. By immunohistochemistry, strong reactivity was observed in the mucosal epithelium of the stomach, small intestine, and colon of both rodents and humans. In the small intestine, there was prominent p185neu expression by mucosal epithelium of the villus, with little or no staining in the crypts. Prominent expression was observed in the liver parenchyma, the endocrine and exocrine portions of the pancreas, and in the salivary gland. Immunoreactive p185neu was also demonstrated in fetal human intestinal epithelium. Tissue sections of selected benign and malignant colonic neoplasms were also examined. Immunoreactivity was consistently greater in adenomatous polyps than in adjacent normal colonic epithelium or areas showing malignant degeneration. By radioimmunoprecipitation, there was decreased expression in cell lines derived from more anaplastic colonic tumors. The p185neu protein is expressed widely in normal and transformed epithelial tissues of the digestive tract of the adult rat and human. This finding suggests that p185neu, a putative growth factor receptor, may play a role in the regulation of normal growth and function or in the malignant transformation of these cells.