Rats were fed up to 9 months diets supplemented with vitamin A in an amount that, by itself, had no apparent adverse effect on the liver. When associated with chronic ethanol administration, vitamin A supplementation strikingly exacerbated ethanol-induced abnormalities: fat accumulation was increased and numerous giant mitochondria were observed. Furthermore, lesions appeared which ethanol alone does not produce in rats, namely necrosis, inflammation, and fibrosis. Vitamin A supplementation increased the number of fat storing cells (lipocytes) which positively correlated with vitamin A accumulation in the liver. However, when vitamin A supplementation was combined with ethanol administration, vitamin A levels in the liver and the number of fat storing cells decreased and numerous myofibroblasts appeared in association with abundant collagen fibers. There was also hepatic inflammation and necrosis, accompanied by a rise in serum glutamate dehydrogenase, SGOT, and SGPT and a decrease in retinol binding protein and vitamin A. We conclude that amounts of vitamin A, which by themselves appear harmless, may produce severe liver lesions when associated with chronic ethanol consumption.