OBJECTIVE The local deposition of fibrinogen and other plasma products from tears within corneal wounds and the expression of plasminogen activator by corneal epithelial cells suggest that the coagulation and fibrinolytic systems play an important role in corneal wound healing. The authors used mouse lines deficient in plasminogen (Plg), fibrinogen (Fib), or both to elucidate the roles of these key fibrinolytic and coagulation factors in the healing of corneal epithelial defects. METHODS Mice were anesthetized, and corneal epithelial defects (3 mm) were created with a blade. The authors conducted histologic examination and immunohistochemical analysis on the healing of injured corneas. RESULTS The corneal epithelial defects of wild-type mice with transparent corneas healed quickly in 7 days, whereas the healing of plasminogen-deficient mice was impaired and complicated by severe and persistent inflammatory responses, the formation of retrocorneal fibrin deposits, corneal cloudiness caused by scar-tissue formation, and often stromal neovascularization. To determine whether these defects in corneal wound repair were specifically related to an impediment in fibrinolysis, corneal wound healing was compared in mice with a combined deficiency in plasminogen and fibrinogen. The loss of fibrinogen in mice lacking plasminogen resulted in the restoration of normal healing with transparent corneas in 7 days, similar to that of wild-type mice. CONCLUSIONS These results provide direct evidence that hemostatic factors play a crucial role in corneal wound repair despite the lack of local hemorrhage. Furthermore, they demonstrate that the essential role of plasmin in corneal would healing is fibrinolysis. It prevents the adverse inflammatory responses caused by prolonged fibrin and fibrinogen deposition in injured corneas.