Although active hepatocellular function is depressed during sepsis, it is not known whether this occurs in the very early stages of sepsis and whether it is due to depressed cardiac output or hepatic blood flow. To study this, rats were subjected to sepsis by cecal ligation and puncture and hepatocellular function was determined at various intervals thereafter by assessing the ability of the liver to clear different doses of indocyanine green. The indocyanine green concentration was continuously measured in vivo with a fiberoptic catheter and an in vivo hemoreflectometer. Maximal velocity and kinetic constant of the clearance of indocyanine green, hepatic blood flow, and cardiac output were determined in experimental and sham-operated rats. The results demonstrate that hepatic blood flow and cardiac output increased 2 to 10 hours after cecal ligation and puncture, while hepatocellular function (maximum velocity and kinetic constant) was decreased even 2 hours following cecal ligation and puncture. No linear correlation between hepatocellular function and hepatic blood flow or cardiac output was found under such conditions. The extremely early depression in active hepatocellular function, despite the increased hepatic blood flow and cardiac output, may form the basis for cellular dysfunctions leading to multiple organ failure during sepsis.