OBJECTIVE Recent observations suggest a role for lymphocytes in human pancreatitis. However, existing animal models of pancreatitis are not immunologically based. In studies on major histocompatibility complex (MHC) II-deficient mice backcrossed five generations onto a C57BL/6 background, we discovered a progressive wasting disease due to pancreatic damage. The purpose of this study was to characterize this model of immune-based pancreatic injury. METHODS The pathology was characterized histologically and functionally by assaying for pancreatic enzymes and glucose. RESULTS By 6 months, a periductal lymphocytic infiltrate was observed that later developed into pancreatic lesions with extensive, but selective, destruction of acinar cells. Mice eventually lost weight, developed a hunched appearance, and began to pass large, pale pellets. Histology of affected mice revealed pancreatic atrophy with almost complete loss of acinar cells, although islets remained intact. Serum levels of amylase, lipase, and glucose confirmed the selective loss of the exocrine pancreas, with both amylase and lipase levels being significantly decreased in affected mice. However, glucose levels remained unaffected. Adoptive transfer of splenic mononuclear cells to athymic mice was found to transfer the disease. CONCLUSIONS Aged MHC II-deficient mice develop an immune-based pancreatitis with selective loss of exocrine cells and function.