Background: Changes in the fibrinolytic system that occur after cardiac transplantation (CTx) and the factors that influence such changes have been poorly described, yet may be important in determining the varying morphologic features of transplant-related coronary artery disease (TxCAD). Methods: Baseline demographic as well as serial clinical information and plasma fibrinolytic levels were prospectively recorded pre-CTx and at multiple time-points post-CTx in 110 de novo cardiac transplant recipients. Results: We noted a biphasic change in fibrinolytic activity over the first year of CTx with an early immediate decline in plasminogen activator inhibitor-1 (PAI-1) activity (p > 0.001) matched with stable PAP (plasmin) activity corresponding to an "enhanced" fibrinolytic state early post-CTx. This was followed by a significant increase at 6 months (p = 0.004) and 1 year (p < 0.001) in PAI-1 activity concomitant with a significant decline in PAP after 3 months (p = 0.005 at 3 months, p < 0.001 at 6 months, p < 0.001 at 1 year) corresponding to an "impaired" fibrinolytic state late post-CTx. Conclusion: The biphasic nature of the fibrinolytic system observed herein may account for the varying morphologic features of TxCAD. © 2007 International Society for Heart and Lung Transplantation.