Thrombomodulin is a surface protein of vascular endothelial cells. A smaller form of thrombomodulin in blood and urine, the soluble (s)thrombomodulin, appears to be derived from injured endothelial cells or to be proteolytically cleaved from thrombomodulin by proteases. Several in vitro and in vivo studies have suggested (s)thrombomodulin as a marker of endothelial damage. In orthotopic liver transplantation, platelet and leukocyte activation as well as prothrombin activation are suspected of being caused by damaged endothelial cells in the graft liver. We determined (s)thrombomodulin antigen as well as thrombin-antithrombin III complexes, protein C, and antithrombin III activities in the course of 23 orthotopic liver transplantations. Samples were taken at 7 different time-points intraoperatively, as well as out of the perfusate released from the graft liver vein during the flushing procedure with arterial blood prior to the opening of the hepatocaval anastomosis. Levels of (s)thrombomodulin antigen and thrombin-antithrombin III complexes showed a significant increase with reperfusion of the graft liver and levels in the perfusate were higher (both: P = 0.0001) than the corresponding systemic levels. In parallel, antithrombin III decreased significantly with reperfusion and perfusate levels of antithrombin III and protein C activities were lower in the systemic circulation (both: P = 0.0001). In conclusion, high levels of (s)thrombomodulin antigen in the early reperfusion phase and in the perfusate strongly indicate endothelial damage to the graft liver vascular bed, paralleled and followed by signs of prothrombin activation.