We have made a comparison between groups of rats fed ethanol and a diet that received intragastric infusion of ethanol continuously for prolonged periods varying only in the amount of fat in the diet (percentage of total calories as fat was 5, 25, and 35%). A fourth group of rats fed high fat (32% of calories) and a diet marginal in protein, vitamins and minerals was also studied. Control rats were pair-fed dextrose in isocaloric amounts. For rats fed diets containing 5, 25, 32, and 35% fat, the avenge blood alcohol levels achieved were 216,224,266 and 353 mg/100 ml, respectively. Average weight gains of the ethanol fed rats were: 15.4,19.6,14.7, and 14.9 g/week, respectively. Serum alanine aminotransferase (ALT) levels of the ethanol-fed rats averaged 123,292,144, and 213 units/liter, respectively. ALT levels in pair-fed controls for the rats fed 32% fat averaged 62 and those of chow-fed controls averaged 49 units/liter. Comparison of liver biopsy-semiquantHied morphological findings revealed an increased 3–4+ fatty change in the ethanol-fed rats also fed the high fat diets: 6/16, 17/17, 5/6, and 5/7 rats, respectively. Necrosis, zonal or spotty, and inflammation were more common in high fat-fed rats. Moreover, fibrosis was only observed centrilobu-lariy in rate fed diets with varying fat content (5, 25, 32, or 35% of calories): 0/16,10/17, 4/6, and 3/7 rats, respectively, over a 5-mon period of feeding. Electron microscopy showed that (to cells predominated in the scarred areas. The mechanism for the centrilobular necrosis-fibrosis was investigated in rats given a diet of ethanol plus 32% fat diet by measuring the level of adenine nucleotide in repeated liver biopsies in five pairs of rate. There was a significant decrease in liver ATP levels and the total adenylate pool which tended to worsen in serial biopsies over a 4-mon period of ethanol feeding. Energy change did not decrease. Arterial pOj levels determined in four of these ethanol-fed rats were reduced compared to controls (83 ± 9,106 ± 9 mm Hg, respectively, p < 0.001). The results support the conclusion that rats fed high fat diets and ethanol by continuous intragastric infusion develop centrilobular scarring similar to that seen in baboons and man ingesting ethanol. This implies that a high fat diet may be obligatory for ethanol-induced Hver fibrosis to develop in the rat Both Ito cell synthesis of collagen and centrilobular hypoxia may be involved in the pathogenesis of the centrilobular fibrosis.