The pancreases of 17 patients who had cystic fibrosis with and without diabetes mellitus were evaluated at autopsy by routine staining and immunohistochemical methods for insulin, glucagon, somatostatin, and pancreatic polypeptide. Qualitative assessment of the number of islets of Langerhans and the degrees of exocrine pancreatic atrophy, fibrosis, and fat replacement was made for each pancreas. Quantitative assessment of islet composition was performed in 15 of the 17 based on the immunochemical reactivity of each cell type. Nondiabetic patients with cystic fibrosis in the latter part of the first decade of life have classic fibrocystic changes of the pancreas, with some persisting exocrine tissue, islets that appear normal, and prominent nesidioblastosis. The latter process may protect these patients from glucose intolerance. Young adult diabetic patients with cystic fibrosis have total loss of exocrine pancreas with fat replacement, lack of nesidioblastosis, a qualitative decrease in the number of islets, fibrosis of and amyloid deposits in islets, decreased numbers of insulin-containing cells in each islet, and atrophy of islet cells, probably resulting from progressive ischemia. Although the potential exists for an increasing incidence of diabetes mellitus in patients with cystic fibrosis as their life spans increase, individual variation occurs in this disease.