The pancreases of 23 patients (mean age 10.5 years, range 5-22) years dying of cystic fibrosis (CF) were evaluated at autopsy by routine histology and immunostaining for changes in their endocrine cell compartment. The severely altered pancreatic tissues showed end stage CF, with either a fibrotic pattern (CF-FIB, n = 14) or a lipoatrophic pattern (CF-LIP, n = 9) prevailing. In all specimens, irrespective of the dominating pattern, the islet system was affected by marked periinsular and intrainsular sclerosis. Quantitatively, the volume densities (relative tissue components) of the parenchymal, fibrotic, fatty and total endocrine compartments as well as the four islet cell types (B, A, D, PP) were determined by point counting. Compared with controls, the CF patients (including two patients with overt diabetes and glucose intolerance, respectively) had a significantly decreased insulin (B)-cell ratio (from 64.4 to 34%) with a concomitant rise in non-B-cells (A-cells: 23.2 to 35%; D-cells: 10.4 to 22%; PP-cells; 2 to 9%). Comparison of endocrine cell ratios in CF-FIB pancreases with CF-LIP pancreases revealed no significant differences. The reduction of approximately 50% of insulin cells in CF patients with advanced disease supports the concept that destruction of exocrine tissue with concomitant fibrous disorganization of islets gradually changes the proportional distribution of the endocrine cells in favor of the noninsulin cells. This slowly ongoing process probably provides the basis for islet dysfunction, i.e. diabetes, increasingly observed in final stage CF.