Although studies have indicated that hepatocellular function is depressed early after the onset of sepsis, it remains unknown whether liver endothelial cell function is also compromised under such conditions. To study this, male rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP), followed by administration of 3 ml/100 g body wt normal saline subcutaneously to these and to sham-operated animals. Blood samples (0.2-ml aliquots) were taken from the carotid artery, portal vein, and hepatic vein at 2, 5, 10 (i.e., hyperdynamic sepsis), or 20 hr (hypodynamic sepsis) after CLP, and plasma hyaluronic acid (HA) was determined using a Pharmacia assay kit. In addition, HA clearance was assessed at 5, 10, or 20 hr after CLP by injecting 30 micrograms/100 g body wt HA intravenously. Plasma HA was determined at 2-40 min after the administration of HA. The results indicate that plasma levels of HA in blood from three different sites did not increase significantly until 10 hr after CLP. Clearance of HA decreased only at 20 hr after CLP, compared to sham-operated animals. These results suggest that the increased plasma levels of HA at 10 hr after the onset of sepsis are solely due to the increased release/production of the polysaccharide. Since circulating HA is cleared exclusively by the liver endothelial cell, the results demonstrate that liver endothelial cell dysfunction (i.e., the increased circulating HA levels and decreased HA clearance) occurs only during the late, hypodynamic stage of polymicrobial sepsis.