Protoporphyria is an inherited disorder in man characterized by the overproduction of protoporphyrin, a compound that is excreted by the liver. Hepatobiliary disease may occur in protoporphyria, and several cases have been reported in which death was due to liver disease. Based on the histological evaluation of liver biopsy specimens from 18 patients, 6 of whom died with cirrhosis and liver failure, we speculate that liver disease in this condition is caused by protoporphyrin deposits in hepatobiliary structures. These deposits are composed of crystals and have a characteristic birefringence when examined by polarization microscopy.One patient with early liver damage was given cholestyramine and vitamin E in an attempt to reduce the amount of protoporphyrin which the liver excreted daily. Liver function tests returned to normal, and red cell and plasma protoporphyrin levels decreased. A repeat liver biopsy after one year of therapy showed healing, with decrease of the protoporphyrin deposits.Liver disease in protoporphyria may be treated by directing therapy toward the metabolic abnormality.