Rational: Severe sepsis is associated with an exacerbated procoagulant state with a protein C system impairment. In contrast, the inflammatory and coagulation status of non-septic organ failure patients is less documented. Objectives: To compare coagulation activation, focusing on protein C system, and inflammatory status in septic and non-septic organ failure patients. Methods: Thirty severe sepsis patients and 30 non-septic patients where recruited at the onset of organ failure and compared to 30 matched healthy subjects. We performed an extensive analysis of the protein C pathway, including plasma proteins measurements and quantification of leukocyte expression of protein C system receptors. In addition, we analyzed the inflammatory status, based on inflammation-related gene leukocyte expression. Measurements and main Results: We observed coagulation activation, reflected by a similar increase in tissue factor mRNA expression in the two patient groups when compared to the healthy subjects. Soluble thrombomodulin levels were higher in septic patients than in healthy controls, while protein C, protein S and soluble EPCR levels were lower. Similar results were obtained in non-septic patients with organ failure. Monocyte thrombomodulin overexpression, along with increased circulating levels of activated protein C, suggest that the capacity for protein C activation is at least partly preserved in both settings. No difference in the inflammatory profile was found between septic and non-septic patients. Conclusions: The pathogenesis of organ failure in critical-care patients is therefore characterized by an overwhelming systemic inflammatory response and by exacerbated coagulation activation, independently of whether or not infection is the triggering event. ClinicalTrials.gov NCT00361725