The relationship between pancreatic duct pressure, bile, bacterial infection of bile, and the development of acute pancreatitis was studied in a feline model. The cat main pancreatic duct was perfused from the head to the tail of the gland with bile and/or Escherichia coli bacteria at "basal" pancreatic duct pressure (< 10 cm H2O) and at pancreatic duct pressure in the upper physiologic range (45 cm H2O). Sterile bile and sterile control solution produced no inflammatory alterations at either pressure. Infected control solution caused a mild acute edematous pancreatitis under low and high pressure. Infected bile caused a severe acute edematous pancreatitis at basal duct pressure; at high pressure, additional focal acinar necrosis was observed in the majority of animals. Infected bile was found to raise basal pancreatic duct pressure by 30%. The other test solutions, which caused only mild inflammatory alterations of the pancreas, did not alter duct pressure. We conclude: (1) Bacterial infection is important for the initiation of acute pancreatitis in this model. (2) High physiologic duct pressure may result in the conversion of nondestructive forms of the inflammation to acinar necrosis. (3) Infected bile-induced increase in duct pressure is likely to result from compression of the duct lumen by the inflammatory edema of the gland.