Cystic fibrosis is characterized by the elaboration of abnormal, thick, tenacious mucus resulting in obstructive disease in sites such as the lung and pancreas. In the pancreas, acinar plugs of mucus have been reported as the earliest recognizable morphologic lesion in cystic fibrosis. Since mucus is not normally elaborated within the pancreatic lobular tissue, the mechanism of accumulation of mucus in acini is enigmatic. To investigate this phenomenon, well-preserved autopsy pancreatic tissue was studied ultrastructurally. This study demonstrated very prominent mucous metaplasia in these diseased organs. Acinar plugs, though, developed before mucous metaplasia. Subsequent histochemical study was performed, which demonstrated that the early acinar plugs exhibited the same staining properties as zymogen granules and were distinct from the staining pattern of mucus in pancreatic tissue of cystic fibrosis patients. These findings, then, indicate that zymogen material, not mucus, becomes inspissated in the acini of the pancreas in early cystic fibrosis, and that subsequent mucous metaplasia occurs as the obstruction and exocrine atrophy progress.