Hepatic endothelial cell damage was evaluated in patients following liver transplantation using 2 serum markers: hyaluronic acid (HA), which measures hepatic endothelial cell function, and factor VIII related antigen (VIIIRAg), an indicator of generalized endothelial damage. HA was elevated in rejection (median 22.3 x control) when compared with stable patients (3.7 x control; P less than 0.00001) and those with posttransplant complications not related to rejection (6.8 x control; P less than 0.0005). The highest levels were seen in patients with chronic rejection (28.7 x control). Levels were also elevated in acute rejection (21.3 x control), and the highest levels in this group were seen in patients who subsequently developed chronic rejection (25.2 x control). Serial studies demonstrated that HA increased 24 hr before serum bilirubin in patients developing acute rejection. VIIIRAg was elevated in all posttransplant patients with no significant difference between rejection and other complications. These results show that hepatic endothelial dysfunction occurs during acute and particularly chronic rejection of liver allografts suggesting that VECs may be an important target of the immune response. Measurement of HA may allow for the early diagnosis of acute rejection and the identification of patients at risk of developing chronic rejection.