There is evidence that the pancreatic duct plays an important role in the evolution of necrotizing pancreatitis. We hypothesized that occlusion of the pancreatic duct and its smaller ductules with prolamine (Ethibloc) in opossums at risk of severe necrotizing pancreatitis would have a beneficial effect on the progression of the disease. Sixteen opossums underwent bile duct ligation below the entrance of the pancreatic duct. They were divided into four groups at 6 days. Group I (control, n = 5) opossums were killed for histologic observation of the degree of necrosis of the pancreas; group II (n = 5) underwent external drainage of the pancreatic biliary duct; group III (n = 4) had external biliary drainage and ligation of the pancreatic duct; group IV (n = 7) was treated with external biliary drainage and ligation of the main pancreatic duct after instillation of prolamine. Serum amylase, lipase, and calcium values were determined. The pancreas was examined by inspection and histologically at the time of death, and the severity of the disease was determined by quantitation of pancreatic tissue necrosis. All animals in groups II and III died 8 to 14 days after bile duct ligation, and all had severe necrotizing pancreatitis. All animals in group IV survived and were killed at 2 to 10 weeks after prolamine (Ethibloc) injection into the pancreatic duct. A mild edematous pancreatitis was observed in all seven animals. Prolamine (Ethibloc) provided dramatic protection from progressive necrosis. This study does not provide an explanation, but it allows for speculation that ductal injection interrupted the deleterious effect of proteolytic enzymes and their leakage into the interstitial space of the pancreas.