Objedtive. To establish an acute lethal liver injury mouse model induced by LPS/D-GalN with NF-κB transgenic mouse. Method. To establish an acute lethal liver injury mouse model by i.p. injection of LPS/D-GalN, then to observe the change of serum inflammatory cytokines and activity of NF-κB. Also, function and pathologic changes of liver were checked. Result The acute lethal liver injury mouse induced by LPS/D-GalN lives for 8-10h, and serum levels of TNF-α, IL-6 and MCP-1 increased significantly and peaked in 2-4 hours. Gross examination of the liver of acute lethal liver injury mouse showed a marked congestion and hemorrhage, Also, the liver sections stained by H&E showed that LPS/D-GalN-induced necrosis of hepatocytes, in which the structure of the liver lobules was destroyed and serious necrosis of hepatocytes and hemorrhage occurred. The levels of serum ALT and AST continued rapid rise in acute lethal liver injury mouse. On the whole, NF-kB activities significantly increased, which peaked in 4-6 hours after challenged with LPS/D-GalN. There no such changes in normal control. Conclusion LPS/D-GalN induced acute lethal liver injury model successfully establishedin NF-κB transgenic mice.