It is well known that ethanol pre-exposure sensitizes the liver to LPS hepatotoxicity. The mechanisms by which ethanol enhances LPS-induced liver injury are not completely elucidated, but are known to involve an enhanced inflammatory response. Ethanol exposure also increases the metabolic rate of the liver and this effect of ethanol on liver is mediated, at least in part, by the sympathetic hormone, epinephrine. However, whether or not the sympathetic nervous system also contributes to the sensitizing effect of ethanol pre-exposure on LPS-induced liver damage has not been determined. The purpose of this study was therefore to test the hypotheses that (i) epinephrine pre-exposure enhances LPS-induced liver damage (comparable to that of ethanol pre-exposure) and that (ii) the sympathetic nervous system contributes to the sensitizing effect of ethanol. Accordingly, male C57BL/6J mice were administered epinephrine for 5 d (2mg/kg/d) via osmotic pumps or bolus ethanol for 3 d (6 g/kg/d) by gavage. Twenty-four h later, mice were injected with LPS (10 mg/kg i.p.). Both epinephrine and ethanol pre-exposure exacerbated LPS-induced liver damage and inflammation. Concomitant administration of propranolol with ethanol significantly attenuated the sensitizing effect of ethanol on LPS-induced liver damage. These data support the hypothesis that the sympathetic nervous system contributes, at least in part, to the mechanism of the sensitizing effect of ethanol. These results also suggest that sympathetic tone may contribute to the initiation and progression of alcoholic liver disease.