We have recently demonstrated that interleukin (IL)-6 is protective against coagulatory and hemostatic disturbance and subsequent pulmonary hemorrhage induced by bacterial endotoxin, at least partly, via the inhibition of proinflammatory cytokines and chemokines using IL-6-null [IL-6(-/-)] mice and corresponding wild-type mice. Its role in fibrinolytic systems remains undefined, however. The present study elucidated the role of IL-6 in the activity of alpha(2)-plasmin inhibitor, an inhibitor of fibrinolysis, during inflammation induced by intraperitoneal administration of lipopolysaccharide in IL-6(-/-) and wild-type mice. Both IL-6(-/-) and wild-type mice were injected with vehicle or lipopolysaccharide (1 mg/kg). Seventy-two hours later, blood samples were collected and alpha(2)-plasmin inhibitor activity was examined. Lipopolysaccharide challenge induced significant enhancement of alpha(2)-plasmin inhibitor activity as compared with vehicle challenge in wild-type mice, but not in IL-6(-/-) mice. In the presence of lipopolysaccharide, the activity was significantly lower in IL-6(-/-) mice than that in wild-type mice. These results indicate that IL-6 can, at least partly, inhibit the lipopolysaccharide-enhanced fibrinolysis via the enhanced alpha2-plasmin inhibitor activity.