The most common cause of the Zollinger-Ellison syndrome is the over-production of a gastrin-like hormone by a non-beta islet cell neoplasm of the pancreas. Hyperplasia and neoformation of islets alone and in combination with neoplasia have been reported in association with the syndrome, but there has been little effort to implicate these findings in the pathogenesis of the Zollinger-Ellison syndrome. Here was presented the findings of nesidioblastosis of islets, proliferation of centroacinar and intercalated duct cells, with discussion of the ultrastructural characteristics of the non-beta granules in the pancreas of a patient having the Zollinger-Ellison syndrome. The findings in this case, together with what is already known, suggest that an extrapancreatic agent is responsible for certain of the histologic changes of the pancreas, which, in turn, may lead to excessive gastrin-production and the Zollinger-Ellison syndrome.