Severe sepsis is a common and frequently fatal condition. Evidence showing a link between the coagulation system and the inflammatory response to sepsis led to the development of drotrecogin alfa (activated) as an agent in the treatment of severe sepsis. Recent studies have shown that the mode of action is actually more complex than initially thought. This recombinant form of the natural anticoagulant, activated protein C, has been demonsrated to reduce mortality in a large randomized controlled, Phase III study involving 1690 patients, even though the results of this and subsequent studies and the licensing of drotrecogin alfa (activated) have generated considerable debate. Administration of drotrecogin alfa (activated) is associated with an increased risk of bleeding and its use is contraindicated in patients with a high risk of bleeding or recent hemorrhagic events.