ExtractSections of pancreas from 16 individuals who died with cystic fibrosis (CF) were classified by morphometric criteria into four categories in increasing order of pancreatic involvement. The concentration of acini, islets, main ducts, lobular ducts, connective tissue, and fat was compared with control levels. The results show that in the least involved pancreases, from neonates who died under 5 months of age, acini were reduced to 33% of control levels and the following were increased: islets, to 410%; lobular ducts, to 250%; and main ducts, to 1700% of controls.With increasing severity of the pancreatic disease the acini were further reduced to 5% and lobular ducts to 37% of control levels, respectively. Main ducts increased by 19‐fold, and fatty infiltration accounted for more than 25% of the fresh weight of the pancreas in 9 of the 16 specimens.Comparative biochemical studies of 35 fibrocystic pancreases were quantitatively related to the severity of the pancreatic involvement as follows. Water and volatile matter, normally accounting for 80±% of the weight of the fresh pancreas, was reduced to less than 30% in the most affected organs. The concentration of zinc diminished from near normal mean levels of 193 &mgr;g Zn/g dry pancreas to 10% of this amount in the severely involved pancreas.Elevated concentrations of calcium, amounting to over 10 times control level, were found in obstructed ductal structures. Calcium was depleted from pancreatic sections adjacent to the obstructions. The following biochemical indicators were significantly different in their mean levels in the 35 fibrocystic pancreases when compared with the 17 controls: (P≤ 0.001) fat, water, zinc, calcium, copper, magnesiu, potassium, and sodium (P≤ 0.01).SpeculationMorphometric and biochemical studies of the pancreas in cystic fibrosis are interpreted to favor an early and perhaps primary role of ductal and ductular abnormality in the pathogenesis of the pancreatic lesion. The principal basis for this suggestion lies in the demonstration of early massive enlargement of the ductular system and the consequent accumulation of viscous calcium‐rich inspissated material responsible for the formation of functional ductal obstructions. Alterations in calcium concentration and binding in the pancreas and in pancreatic juice are believed to be responsible for changes in membrane permeability and the transport of water and electrolytes. The pancreatic disease process beginsin uteroand the degeneration of the pancreas progresses through life in nearly all patients with cystic fibrosis.