Background. Although hepatocellular dysfunction occurs early after the onset of sepsis, the mechanism responsible for this remains unknown. We tested the hypothesis that the reduction in Kupffer cell (KC) numbers prior to the onset of sepsis prevents the occurrence of hepatocellular dysfunction and reduces levels of the proinflammatory cytokines IL-1β and IL-6 during the early stage of polymicrobial sepsis. Materials and methods. The number of KC in male adult rats was reduced in vivo by intravenous injection of gadolinium chloride 48 h before the induction of sepsis. KC-reduced and KC- normal rats were then subjected to cecal ligation and puncture (CLP, i.e., a model of polymicrobial sepsis) or sham operation followed by administration of normal saline solution. At 5 h after CLP (the early stage of sepsis), hepatocellular function [i.e., the maximal velocity of clearance (V(max)) and efficiency of active transport (K(m)) of indocyanine green] was measured using a fiber-optic catheter and in vivo hemoreflectometer. Whole blood was drawn to measure plasma levels of IL.1β and IL-6 using enzyme-linked immunosorbent assays. Results. Hepatocellular function was depressed and the circulating levels of IL-1β and IL-6 were increased significantly at 5 h after CLP. KC reduction by prior administration of gadolinium chloride, however, prevented the occurrence of hepatocellular dysfunction and the upregulation of IL-1β and IL-6. Conclusions. The KC-derived proinflammatory cytokines IL-1β and IL-6 appear to be directly or indirectly responsible for producing hepatocellular dysfunction during early sepsis. Thus, pharmacologic agents that downregulate the production of one or both of these proinflammatory cytokines in the liver may be useful for maintaining hepatocellular function during the early stage of sepsis.