A common epithelial cell surface marker (EPM-1) was defined by two monoclonal antibodies (Pa-25 and Pa-42), raised against a pancreatic tumor cell line (Capan-1). Both monoclonal antibodies were tested on 49 cultured human cell lines and 244 tissue samples and reacted with all 76 tissue samples of 20 different normal epithelial cell types and with 57 of 63 epithelial tumor tissue samples of nonendocrine origin. Included were eight exocrine pancreatic carcinomas. There the percentage of EPM-1 positive tumor cells correlated with tumor grading. EPM-1 was detectable on the cell surface of cultured human cell lines of the pancreas, liver, colon, and mamma. Some epithelial tumor cell lines did not express EPM-1 on the cell surface, but in the cytoplasm. 100 nonepithelial and epithelial endocrine tissue samples as well as 25 nonepithelial cultured tumor and normal cells were unreactive with monoclonal antibodies Pa-25 and Pa-42. These included cells of neuronal, endocrine, and mesenchymal origin. EPM-1 activity was purified from pancreas tumor cells Capan-1 and from human sera by high-performance liquid chromatography and its molecular weight amounts to about Mr 400,000. EPM-1 was detectable in bronchial, intestinal, and pancreatic secretions and saliva and serum by an enzyme-linked immunosorbent assay test. EPM-1 values were high in the sera of normal individuals, but low or not detectable in most sera (21 of 31) of patients with gastrointestinal tumors. EPM-1 represents a novel differentiation marker for epithelial cell types, which should have a central role in the biology of normal and tumorous epithelial cells.