Plasminogen (Plg)-deficient mice experience wasting and have decreased longevity due to disseminated fibrin deposition. We generated mice with combined deficiencies of Plg and coagulation factor IX (fIX) or XI (fXI) to determine the effects on the Plg null phenotype. Mice lacking Plg and fIX (Plg(-/-)/fIX-/-) have lower mortality at age 6 months than Plg(-/-)/fIX+/+ mice (15% and 67%, respectively) and less severe wasting, consistent with the importance of fIX in fibrin formation. In contrast, combined Plg and fXI deficiency (Plg(-/-)/fXI-/-) reduces life span (more than 90% mortality at 6 months) and is associated with leukocyte infiltration of the lungs and pulmonary fibrosis. These abnormalities are not seen in Plg-/- or Plg(-/-)/fIX-/- animals. Activated fXI is thought to function primarily as a fIX activator; however, our observation suggests that fXI may have functions in regulation of inflammation or tissue repair distinct from its role in coagulation.