Thrombomodulin has a pivotal role in the protein C system that is important in the pathogenesis of sepsis. In sepsis, endothelial cell expression of thrombomodulin is strongly downregulated, causing an impaired activation of protein C that is central in the modulation of coagulation activation and inflammatory processes. In addition, thrombomodulin itself has marked immunomodulatory effects, targeting neutrophil adhesion, complement activation and cytokine generation. Several preclinical studies in experimental sepsis models have shown that administration of soluble thrombomodulin is capable of improving the derangement of coagulation, ameliorates inflammatory responses and may restore organ dysfunction. Initial clinical studies in patients with disseminated intravascular coagulation, of whom a significant proportion were patients with sepsis, demonstrate a beneficial effect of recombinant soluble thrombomodulin on restoration of coagulation and improvement of organ failure.