During the past 15 years, several anti-inflammatory treatments have failed to reduce mortality in patients with severe sepsis. However, recent evidence indicates that coagulation abnormalities in sepsis may play a major role in the pathogenesis of multiple organ failure and the high mortality rate in patients with severe sepsis. Interestingly, blockade of the coagulant pathway can inhibit both procoagulant and proinflammatory pathways in sepsis. Protein C, a natural anticoagulant, interrupts several of the pathophysiologic pathways in sepsis. Acquired protein C deficiency is present in the majority of septic patients and is associated with unfavorable outcomes. Protein C replacement therapy was effective in preclinical animal models of sepsis in reducing end-organ damage and mortality. Recent clinical trials of protein C replacement in human meningococcemia resulted in a markedly decreased morbidity and mortality. And, most importantly, in a recently completed large, randomized trial of activated protein C treatment in severe sepsis, mortality was reduced from 30.8% in the placebo group to 24.7% in the treatment group at 28 days. Thus, there is new evidence that mortality can be reduced among patients with severe sepsis through the use of a new therapy that inhibits the procoagulant and the inflammatory cascades.