For the development of an artificial liver support system, a clinically relevant large-animal model of fulminant hepatic failure (FHF) is indispensable. Although several large-animal models have been reported so far, they have not been entirely satisfactory. Recently, we have developed a new porcine model of FHF by means of intraportal administration of 0.1 mg/kg of alpha-amanitin and 1 microg/kg of lipopolysaccharide (LPS). This model has the following superior features: 100% mortality within 5 days along with a marked elevation of aspartate transaminase (AST) levels to around 10,000 IU/l, and severe metabolic disorders such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia; an onset of hepatic encephalopathy and a significant increase in intracranial pressure immediately before death; a reversal of FHF by orthotopic liver transplantation, proving that the toxicity is liver-specific and that the graft liver is unaffected; and the capability of the damaged liver to recover and achieve both morphological and functional regeneration in 1 week if supported by an efficient auxiliary graft. Because this porcine model satisfies many of the required criteria of an optimal FHF model, it is expected to provide a useful tool for the study of FHF and the development of new therapies.