Hepatic ethanol metabolism in the liver from carbon tetrachloride (CCl4)- treated animals was studied using non-recirculating hemoglobin-free liver perfusion system. CCl4-administration decreased ethanol uptake by the liver to 56% and 30% of the control values following the acute (24 hrs. after treatment) and chronic (8-12 weeks) treatments, respectively. In addition, 4 mM fructose, a well-known agent to increase ethanol metabolism in the liver, did not increase the hepatic uptake of ethanol in CCl4-treated livers. Hepatic alcohol dehydrogenase activity was not changed following acute and chronic CCl4 treatments. The lactate/pyruvate (cytosolic NADH/NAD) ratio as well as beta-hydroxybutyrate/acetoacetate (mitochondrial NADH/NAD) ratio significantly increased, whereas both hepatic oxygen uptake and oxidation of NADH in mitochondria remarkably decreased in parallel with the magnitude of liver injury induced by CCl4. Histological studies revealed that the liver had centrilobular coagulative necrosis with fatty droplet formations at acute phase, while bridging fibrosis between central and portal areas and the pattern of cirrhosis with conspicuous changes in the mitochondria were seen at chronic phase. These data indicate that CCl4-treatment significantly reduces hepatic ethanol metabolism via the inhibition of reoxidation of NADH, a rate limiting step of ethanol metabolism in the liver.