Hypermetabolism organ failure syndrome (HOF) appears to represent the onset of clinical hepatic failure after an interval of hypermetabolism in patients experiencing episodes of perfusion failure, sepsis, or persistent foci of inflammation. The data supporting clinical hepatic failure in HOF include: jaundice, cholestasis and biliary sludge; reduced hepatic amino acid clearance and protein synthesis; reduced hepatic redox potential (ButtB/AcAc); increased ureagenesis and increased fat synthesis. The origin of this hepatic failure is unclear. Current research would indicate a dominant role for the Kupffer cell and for the gut. The Kupffer cell appears to be able to modulate hepatic function through release of cytokines and prostaglandins. These cells appear to be increasingly stimulated by such agents as hypoxia, endotoxin and platelet-activating factor. The liver cells also appear to 'talk' to the Kupffer cell and modulate its cytokine release. The hypothesis is now being tested that paracrine amplification may be a mechanism of hepatotoxicity. Nutrition continues to play a dominant role in the support of HOF; after a program of source control and resuscitation, mortality rates have dropped. Nutrition is currently aimed at nitrogen retention in the absence of excess glucose and fat. Early on, nitrogen support at 1.5-2.0 g · kg-1 · day-1 is effective in supporting protein synthesis. The modified amino acids appear to be more efficient at these goals than standard formulas. Future nutrient effects are focused on altering cytokine and arachidonic acid metabolite release from macrophages and on stimulating immune function.