Abstract: Background: Alcoholic steatosis is the early and most common liver disease, and may precede the onset of more severe forms of liver injury.Methods: Here, we tested the effect of Korean Red Ginseng extract (RGE) in two murine models of ethanol (EtOH)-feeding and ethanol-treated hepatocytes.Results and Conclusion: Blood biochemistry analysis demonstrated that RGE treatment improved liver function. Histopathology and measurement of hepatic triglyceride content verified the ability of RGE to inhibit fat accumulation. Consistent with this, RGE administration down-regulated hepatic lipogenic gene induction and restored hepatic lipolytic gene repression by EtOH. The role of oxidative stress in the pathogenesis of alcoholic liver diseases (ALD) is well established. Treatment with RGE attenuated EtOH-induced CYP2E1, 4-hydroxynonenal and nitrotyrosine levels. Alcohol consumption also decreased phosphorylation of AMPK, which was restored by RGE. Moreover, RGE markedly inhibited fat accumulation in EtOH-treated hepatocytes, which correlated with a decrease in SREBP-1 and a commensurate increase in Sirt1 and PPARα expression. Interestingly, the ginsenosides Rb2 and Rd, but not Rb1, significantly inhibited fat accumulation in hepatocytes. These results demonstrate that RGE and its ginsenoside components inhibit alcoholic steatosis and liver injury by AMPK/Sirt1 activation in vivo and in vitro both, suggesting that RGE may have a potential to treat ALD.