Pancreatitis induced by ligation of the pancreatic duct produces morphologic similarities to human pancreatitis. This model is easily performed in big animals, but it is very difficult to perform pancreatic duct ligation in small animals. Many experimental studies of pharmaceutical treatments for pancreatitis used pancreatic duct-ligation models, but it is also difficult to evaluate the efficacy of the drugs used, because the animals used are of different species with individual differences. To overcome these problems, we ligated the main pancreatic duct of the splenic lobe by a 5.0 absorbable suture by using a surgical microscope and left the gastroduodenal lobe intact in the same rats. This model produced damaged pancreatic tissue in one part and normal pancreatic tissue in another part of the pancreas in the same animals, biochemically and histologically. We evaluated the effect of a new protease inhibitor (ONO-3404) on this preliminary model and found this new protease inhibitor demonstrated a hypertrophic effect on the damaged pancreatic tissue and the normal pancreatic tissue in the same animals. This model is also useful to study pharmaceutic treatment for pancreatic insufficiency and to study chemically induced pancreatic carcinogenesis in the damaged pancreatic tissue and the normal pancreatic tissue in the same animals.