Carbohydrate antigen (CA) 19-9 identified by a murine monoclonal antibody against a colorectal carcinoma antigen is thought to be a sialylated Lewis (Le)a blood group antigen and occurs in high concentration in serum of patients with pancreatic carcinoma. This study was designed to identify the relationship between Lewis antigens and CA 19-9 in patients with pancreatic cancer. The following analyses were performed in 20 pancreatic cancer patients: Lea and Leb antigen phenotype in saliva (modified enzyme-linked immunosorbent assay) or on red cells (hemagglutination); CA 19-9 levels (radioimmunoassay) in serum; and CA 19-9 and Lea and Leb expression (immunoperoxidase assay) on tumor tissue. Lea-b- patients based on salivary phenotype failed to express CA 19-9 in tumor tissue and had normal or low levels of CA 19-9 (less than 37 units/ml) in serum (P = 0.0011, versus Lea+b- and Lea-b+ patients). Eighty-eight % of Lea+b- and Lea-b+ patients had elevated serum CA 19-9 levels (greater than 37 units/ml). All Lea+b- and Lea-b+ patients expressed both Lea and Leb antigens in tumor tissue. These results support the view that Lea-b- pancreatic cancer patients cannot manufacture CA 19-9. Surprisingly, Lea-positive patients express Leb antigen in tumor tissue; in this subgroup, Leb antigen may be a tumor-specific biomarker.