The activation of hemostasis and fibrinolysis frequently is observed in allografted organs. Plasminogen is activated by urokinase and tissue plasminogen activator (tPA). We have studied human hearts before and after transplantation to determine if fibrin deposition within the microcirculation is associated with a depletion of myocardial tPA, and if such depletion of tPA is associated with decreased fibrinolysis. We found that tPA in pretransplanted hearts and in biopsies from hearts of most patients with a stable clinical course is confined to arterial and arteriolar smooth muscle cells. The depletion of smooth muscle cell reactivity was associated with microvascular fibrin deposition in unstable allografts, and the appearance of endothelial cell tPA reactivity heralded a bad prognosis. Successful medical management was signaled by a loss of endothelial tPA reactivity and a return of tPA reactivity in arterial and arteriolar smooth muscle cells. These findings indicate a central role for tPA in maintaining the integrity of the microcirculation in transplanted human hearts.