A serum autoantibody to a pancreatic antigen was identified in patients with idiopathic chronic pancreatitis and Sjögren's syndrome by radioimmunoassay and Western immunoblotting. Antigen from porcine and human pancreas extracts was partially purified using a monoclonal antibody, SP3-1, which recognizes the antigen in duct cells of various exocrine organs. Solid phase radioimmunoassay of the pancreatic antigen showed a positive result in 6 of 20 patients with idiopathic chronic pancreatitis (30%), 3 of 11 patients with Sjögren's syndrome (27%), and 1 of 15 patients with alcoholic chronic pancreatitis (7%). Among seven patients with stone-related chronic pancreatitis, six patients with autoimmune thyroiditis, and 14 normal controls, none showed evidence of autoantibodies to the pancreatic antigen. Western immunoblotting showed that serum antibody commonly reacted with a 60-kD molecule of either porcine or human pancreatic antigen, with which SP3-1 also reacted. These results show the existence of the autoantibodies to pancreas, especially to an antigen expressed in ductal cells of exocrine glands, in idiopathic chronic pancreatitis and Sjögren's syndrome, and suggest the possibility of an autoimmune mechanism in the pathogenesis of idiopathic chronic pancreatitis.