Long-term studies of the carcinogenicity of N-methyl-N-nitrosourea (MNU) in inbred guinea pigs were undertaken to develop an animal model of pancreatic adenocarcinoma. MNU, freshly, dissolved in 0.015 M sodium citrate buffer, pH 6.0, was administered by gavage once weekly at a dose of 10 mg/kg body weight to inbred strain 13 guinea pigs. By 27 weeks, 54% of guinea pigs given MNU weekly died, mostly due to severe atrophy and fatty metamorphosis of the exocrine acinar cells of the pancreas. Of 34 guinea pigs that survived more than 27 weeks of MNU administration, 10 (29%) developed pancreatic adenocarcinoma between 28 and 44 weeks. Other tumors included adenocarcinoma of the stomach (two animals) and of colon (one animal), lymphoma of mesenteric nodes (three animals), and a hepatoma (one animal). Atypical changes involving acinar cells were observed in certain pancreatic lobules and included ductular or pseudoductular transformation, acinar ectasia, increased mitotic activity, and periacinar fibrosis. These changes are suggestive of acinar cell dedifferentiation, and their role, if any, in the histogenesis of pancreatic adenocarcinoma remains to be elucidated. These studies suggest the feasibility of using inbred guinea pigs for developing a satisfactory model of pancreatic adenocarcinoma. Additional studies are necessary to minimize the high mortality rate during the first 6 months and to enhance the incidence of pancreatic adenocarcinoma.