Abstract The relationship between pancreatic duct pressure, duct permeability to macromolecules and the development of acute pancreatitis was studied in a cat model. Perfusion of the pancreatic duct with 15 mM glycodeoxycholic acid, ethanol administration, or secretagogue-stimulated pancreatic secretion against > 50 per cent duct obstruction resulted in an increase in peak pancreatic duct pressure in all animals. Duct permeability to 20 000 molecular weight dextran molecules was increased in 22 of 29 experimental animals compared with two of 22 control animals (P <0·01). Perfusion of the pancreatic duct with activated pancreatic enzymes resulted in acute pancreatitis in 24 of 29 experimental animals compared with three of 22 control animals (P <0·01). These results suggest that pancreatic ductal hypertension, resulting in increased ductal permeability to large molecules, may be a common early event in gallstone and alcoholic pancreatitis.