Influenza accounts for 5-10% of community-acquired pneumonia cases, and is a major cause of mortality. Sterile and bacterial lung injury are associated with procoagulant and inflammatory derangements in the lungs and down-regulation of the protein C (PC) pathway has been correlated with disease severity and mortality in severe bacterial pneumonia and sepsis. In addition, during lethal influenza pneumonia, pulmonary and systemic coagulation are activated, which can be attenuated by the administration of recombinant activated (A) PC. We here determined the role of endogenous PC in lethal H1N1 influenza A infection. Male C57BL/6 mice pretreated with an inhibitory monoclonal antibody directed against murine PC or a control antibody were intranasally infected with a lethal dose of a mouse-adapted H1N1 influenza A strain. Mice were killed at 48 or 96 hours after infection, after which lungs and bronchoalveolar lavage fluid were harvested, or observed for up to 9 days. Anti-PC antibody treatment aggravated pulmonary activation of coagulation as compared with control antibody treatment, as reflected by increased lung concentrations of thrombin-antithrombin complexes and fibrin degradation products, as well as intravascular thrombus formation. Anti-PC antibody treatment aggravated lung histopathology, but lowered bronchoalveolar neutrophil influx and total protein levels, and delayed mortality. In conclusion, endogenous PC has strong effects on the host response to lethal influenza A infection, inhibiting pulmonary coagulopathy and inflammation on the one hand, but facilitating neutrophil influx and protein leak and accelerating mortality on the other hand.