The incidence of fasting hyperglycemia and diabetes mellitus (DM) in older patients with cystic fibrosis (CF) is reported to be 8%, but few quantitative studies of the islets of Langerhans in this disease have been done. Three groups of patients were studied in this morphometric autopsy analysis: patients with CF and insulin-dependent DM (n = 7), normoglycemic patients with CF (n = 4), and age-matched adolescents and young-adult controls (n = 11). The islets of Langerhans were stained with immunoperoxidase for insulin, glucagon, and somatostatin. The percentage of the total islet surface area occupied by each immunoperoxidase positive cell type was determined by a point-counting method. The mean percent surface area occupied by insulin-producing cells (28.3%) in diabetics with CF was significantly less than normoglycemics with CF (46.7%) and controls (53.4%). The mean percent surface area occupied by glucagon-producing cells was similar in all three groups: 21.9% in CF diabetics, 25.4% in normoglycemics with CF, and 22.4% in controls. The mean percent surface area occupied by somatostatin was increased in both CF groups compared with controls: diabetics with CF, 29.3%; normoglycemics with CF, 26.2%; and controls, 15.5%. These findings correlate with published clinical endocrine studies of hyperglycemia in CF. Endocrine cell quantitation in diabetics with CF differs from that in both juvenile (type 1) and adult-onset (type 2) DM.