Previous studies have shown that the DU-PAN-2 antigen is elevated in approximately 70% of serum samples obtained from pancreatic adenocarcinoma patients, and within the normal range (less than 400 U/ml) in 99% of normal subjects. In this study, the DU-PAN-2 antigen level of the serum and pancreatic ductal fluid in patients with malignant pancreatic disease were compared to antigen levels in patients with benign pancreatic diseases. Six percent of patients with chronic pancreatitis and 13% of patients with severe acute pancreatitis had elevated DU-PAN-2 antigen levels in their sera. Pancreatic ductal fluid DU-PAN-2 levels were elevated in 33% (11 of 33) of patients with pancreatic adenocarcinomas, whereas 16% (5 of 31) of patients with chronic pancreatitis and 38% (8 of 21) of control patients had elevated secretion levels. Unlike DU-PAN-2, the tumor markers carcinoembryonic antigen (CEA) and carcinoma (CA) 19-9 were elevated in 90 and 100%, respectively, of secretions of patients with pancreatic adenocarcinoma. However, CEA and CA 19-9 ductal fluid levels were also elevated in patients with chronic pancreatitis (CEA: 61%; CA 19-9: 85%), and therefore these markers are not helpful in distinguishing benign from malignant pancreatic disease. The physiologic implications of elevated DU-PAN-2 serum antigen levels in patients with normal ductal fluid DU-PAN-2 levels are discussed.