Because of its central role in metabolism and host defense mechanisms, the liver is thought to be a major organ responsible for the initiation of multiple organ failure during sepsis. It is, therefore, important to discuss whether hepatocellular dysfunction occurs during early sepsis and, if so, whether this occurs prior to hepatocellular damage as evidenced by elevation in serum enzyme levels. Because indocyanine green clearance has been demonstrated to be an early and extremely sensitive measure of active hepatocyte transport function, a technique for repeated measurement of hepatocellular function by in vivo indocyanine green clearance was developed in small animals, such as the rat. Studies have indicated that hepatocellular function is markedly depressed during early stages of polymicrobial sepsis despite the increased cardiac output and hepatic blood flow and decreased peripheral vascular resistance. The depression in hepatocellular function in early, hyperdynamic stages of sepsis does not appear to be due to any reduction in hepatic perfusion but is associated with elevated levels of circulating proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. Furthermore, administration of recombinant murine TNF-a at a dose that does not reduce cardiac output and hepatic perfusion produces hepatocellular dysfunction and increases plasma levels of IL-6. Thus upregulation of TNF and/or IL-6 may be responsible for producing hepatocellular dysfunction during early, hyperdynamic stages of sepsis. cecal ligation and puncture; indocyanine green clearance; hemodynamics; hepatic perfusion; fluid resuscitation; tumor necrosis factor; interleukin-6 Copyright ©1996 the American Physiological Society.