This study examines the generation of superoxide anion by the perfused rat liver after ethanol intoxication and acute endotoxemia to assess the potential importance of oxygen-derived free radicals in the ethanol-induced hepatic pathological condition. Hepatic superoxide anion production of 0.65 ± 0.06 nmol/min/gm liver weight was measured 1 hr after ethanol infusion; it reached a peak value of 0.8 ± 0.07 at 3 hr and was reduced to 0.11 ± 0.01 by 7 hr. In a group of animals, 4-methylpyrazole was injected 5 min before the administration of ethanol to determine whether the metabolism of ethanol moiety is necessary for the observed effects. However, no significant inhibition of superoxide production was observed after 4-methylpyrazole administration. Introduction of ibuprofen into the perfused liver abolished superoxide anion production, suggesting that arachidonic acid metabolites may play an important role in superoxide generation under these conditions. Endotoxin, a potent activator of macrophages, has also been associated with increased superoxide release by the liver. Therefore the combined impact of ethanol and endotoxin on superoxide production by the liver was also examined. Acute ethanol intoxication inhibited the endotoxin-mediated superoxide anion generation by the perfused liver. These data indicate that the ethanol-mediated superoxide production and the ethanol-induced inhibition of the lipopolysaccharide-enhanced free-radical generation by the liver may have a pathophysiological significance in tissue injury and in resistance to infection. (HEPATOLOGY 1992;15?-898).