The thrombomodulin-protein C-protein S (TM-PC-PS) pathway exerts anticoagulant and anti-inflammatory effects. We investigated the role of TM in the pulmonary immune response in vivo by the use of mice with a mutation in the TM gene (TM(pro/pro)) that was earlier found to result in a minimal capacity for activated PC (APC) generation in the circulation. We here demonstrate that TM(pro/pro) mice also display a strongly reduced capacity to produce APC in the alveolar compartment upon intrapulmonary delivery of PC and thrombin. We monitored procoagulant and inflammatory changes in the lung during Gram-positive (Streptococcus pneumoniae) and Gram-negative (Klebsiella pneumoniae) pneumonia and after local administration of lipopolysaccharide (LPS). Bacterial pneumonia was associated with fibrin(ogen) depositions in the lung that colocalized with inflammatory infiltrates. LPS also induced a rise in thrombin-antithrombin complexes in bronchoalveolar lavage fluid. These pulmonary procoagulant responses were unaltered in TM(pro/pro) mice, except for enhanced fibrin(ogen) deposition during pneumococcal pneumonia. In addition, TM(pro/pro) mice displayed unchanged antibacterial defense, neutrophil recruitment, and cytokine/chemokine levels. These data suggest that the capacity of TM to generate APC does not play a role of importance in the pulmonary response to respiratory pathogens or LPS.