This study tests two hypotheses: (1) prior exposure to LPS induces cross-tolerance for the hepatic effects of subsequent short-term alcohol intoxication; and (2) short-term alcohol intoxication renders the liver resistant to the effects of acute endotoxemia, resulting in reduced production of superoxide and tumor necrosis factor. In the first group of experiments, male Sprague-Dawley rats were treated intravenously with E. coli lipopolysaccharide (LPS) (0.5 mg/kg) 48 hr before they were given an intravenous bolus of ethanol (1.75 g/kg), followed by 250-300 mg/kg/hr) for 3-5 hr. Superoxide release in the perfused liver was measured after 3-hr ethanol infusion. Pretreatment with LPS attenuated ethanol-mediated superoxide anion release by the perfused liver. The stimulatory effect of phorbol myristate acetate on hepatic release of superoxide was also decreased. In the second group of experiments, rats previously treated with ethanol for 5 hr, received an intravenous injection of LPS (1 mg/kg). At 90 min after LPS, sera were collected for tumor necrosis factor alpha assay. Hepatic release of superoxide anion was determined 3 hr after LPS. Acute ethanol intoxication for 5 hr significantly reduced LPS-induced serum tumor necrosis factor activity and free radical release by the perfused liver. LPS-induced mortality was also decreased. In both groups of experiments serum corticosteroid levels were reduced during cross-tolerance. These results demonstrate that cross-tolerance develops between acute alcohol intoxication and endotoxemia manifesting in reduced hepatic production of cytotoxic cytokines and superoxide anions.