Oxidative stress has been implicated in the propagation of acute liver injury. The aim of our study was to investigate whether gene transfer of alpha-melanocyte-stimulating hormone (alpha-MSH), a potent anti-inflammatory peptide, could prevent fulminant hepatic failure in mice. Acute liver damage was induced by intraperitoneal administration of thioacetamide. Hydrodynamics-based gene transfection with alpha-MSH expression plasmid via rapid tail vein injection was initiated 1 day prior to intoxication. The mortality in the alpha-MSH-treated mice was significantly lower compared to the vehicle group 3 days after injury. Liver histology significantly improved and TUNEL-positive hepatocytes decreased in the treated mice. The degradation of IkappaBalpha, endogenous inhibitor of nuclear factor kappaB, and upregulation of inducible nitric oxide synthase and tumor necrosis factor-alpha mRNA levels were prevented in the alpha-MSH-treated group, indicating decreased oxidative stress and inflammation. These results suggest alpha-MSH gene therapy might protect against acute hepatic necroinflammatory damage with further potential applications.