Thrombomodulin (TM), which is located in the surface of the endothelium in the arteries, veins, and capillaries of major organs such as the brain, lungs, liver, kidneys, skeletal muscles, and gastrointestinal tract, is one of several indicators of endothelial injury. Von Willebrand factor (vWf), which is synthesized by endothelial cells, is also an endothelial specific glycoprotein. The serum level of vWf increases in response to various stimuli without endothelial injury. An elevated serum level of vWf may suggest endothelial activation in severe head injury. We hypothesize that the degree of cerebral endothelial activation or injury depends on the type of head injury and that measuring the TM and vWf is useful for predicting delayed traumatic intracerebral hematoma (DTICH), produced by weakness of the vessel wall, occuring either as a direct or indirect effect of head injury. The values of vWf in focal brain injury (ranging from 332.5 +/- 52.8% to 361.7 +/- 86.2%) were significantly higher than those in diffuse axonal injury from 2 h to 7 days after the injury occurred (ranging from 201.6 +/- 59.5% to 242.5 +/- 51.7%). The serum level of TM in focal brain injury (ranging from 3.84 +/- 1.54 to 4.12 +/- 1.46 U/mL) was higher than that in diffuse axonal injury (ranging from 2.96 +/- 0.63 to 3.67 +/- 1.70 U/mL), but these differences were not statistically significant. In patients with DTICH, TM was significantly higher than in patients without DTICH (p < 0.01). The results of our study demonstrate that the degree of endothelial activation in focal brain injury was significantly higher than in diffuse brain injury. In addition, the serum level of TM in patients with DTICH was significantly higher than in patients without DTICH. These findings suggest that cerebral tissue injury is often accompanied by cerebral endothelial activation, and that these two phenomena should be distinguished from each other. The levels of serum TM and vWf appear to be good indicators of the cerebral endothelial injury and of endothelial activation in severe head injury.