The Long-Evans Cinnamon rat is a mutant strain that contracts hereditary hepatitis and, eventually, spontaneous hepatocellular carcinoma. Because we found a corresponding gross copper accumulation in the liver of the rats, we examined whether the development of hepatitis in our rat system could be prevented by administration of D-penicillamine. D-Penicillamine is a copper-chelating agent and one of the drugs effective for human Wilson's disease, in which abnormal copper metabolism is also observed. The results show that D-penicillamine treatment inhibited the elevation of serum transaminases, suppressed abnormal histological changes in the liver and completely prevented the onset of hepatitis in the Long-Evans Cinnamon rats. We further found that the copper concentration in the liver and serum copper and ceruloplasmin levels were decreased, whereas the urinary copper level was increased in the D-penicillaminetreated LongEvans Cinnamon rats. These findings demonstrate that the pathogenesis of hereditary hepatitis in Long-Evans Cinnamon rats is due to abnormal copper accumulation in the liver. (HEPATOLOGY 1992;15:82-87.) Two inbred strains of rats, Long-Evans Cinnamon (LEC) and Long-Evans Agouti (LEA), were established from a closed colony of Long-Evans rats. The LEC rats, compared with LEA rats, spontaneously contract acute hepatitis with jaundice around the age of 4 mo; half die of fulminant hepatitis. Those that survive exhibit chronic hepatitis and, eventually, cholangiofibrosis and HCC (1-3). Genetic analysis of LEC rats has revealed that a single autosomal recessive gene is responsible for the hepatitis (2, 4). The hepatitis in LEC rats was not suppressed under immunosuppressed conditions by