As stated in RFA-AA02-005, investigations are needed on pharmacological agents that prevent or replace alcohol-related morbidity. In this regard, alcoholic hepatitis is a major cause of alcohol-related morbidity and mortality in the US and in the world in large part due to a lack of effective treatment options for this condition. Prior studies from this group of investigators using complimentary approaches including in vitro studies and human pilot data, supports the concept that the cytokine, tumor necrosis factor (TNF), plays a pathogenic role in the development of alcoholic hepatitis and that neutralization of TNF may be effective in ameliorating the clinical syndrome of alcoholic hepatitis. In this proposal, we will expand on these preliminary studies by testing the hypothesis that the soluble TNF neutralizing agent, etanercept, is safe and effective in treating patients with alcoholic hepatitis by reducing TNF/IL-6 dependent inflammation. In Aim 1, we will conduct a Phase II, double-blind randomized controlled study, which will include patients with moderate or severe alcoholic hepatitis as defined by a specified MELD (Mayo Endstage Liver Disease) score and incidence of infectious adverse events. Patients will receive etanercept or placebo twice a week for a period of up to three months. The primary endpoint of this study will include mortality as assessed by one-month and six-month survival. Secondary endpoints will include change in MELD score. In Aim 2, we will measure serial serum TNF bioactivity, IL-6 levels, and serum markers of inflammation (C-reactive protein and serum amyloid A protein) and hepatocyte regeneration (hepatocyte growth factor and transforming growth factor alpha) in control and treated patients before and after the study protocol. TNF bioactivity will be assessed by an in vitro cytotoxicity assay. Serum markers will be measured by ELISA. Thus, this study, submitted by a group of investigators with extensive experience in alcoholic liver disease and TNF, will determine the potential efficacy of a novel and innovative therapeutic approach, etanercept, in patients with alcoholic hepatitis. Additionally, the proposed mechanistic analyses will provide correlative information regarding a potential IL-6 dependent mechanism of benefit of etanercept in patients with alcoholic hepatitis, thereby advancing our understanding of this devastating condition.