An attempt was made to develop an animal model for the study of the etiology of noncirrhotic portal fibrosis or idiopathic portal hypertension based on the assumption that it is related to chronic abdominal infection. Rabbits were given killed nonpathogenic Escherichia coli intraportally or intravenously. The animals to which a mixture of killed E. coli and rabbit antiserum (aggregated E. coli) was given intraportally developed remarkable histologic changes in the liver. The early inflammatory reactions in the portal area and parenchyma were followed by rapid disappearance of inflammation and development of portal fibrosis with bile duct proliferation. Three intraportal challenges with aggregated E. coli were sufficient to produce pronounced portal fibrosis, although there was considerable variation in response among individual animals. This procedure also produced splenomegaly, and in some animals marked portal hypertension. Injection of nonaggregated killed E. coli into the portal vein or aggregated E. coli into the ear vein also caused similar hepatic changes, but they were milder in degree. These histologic changes resemble portal fibrosis seen in idiopathic portal hypertension and, less closely, pericholangitis associated with inflammatory bowel disease in humans.