Cardiac allograft failure is most commonly caused by acute rejection and cardiac allograft vasculopathy. Consequently, heart transplant recipients who present with heart failure are empirically treated at many transplant centers with augmented immunosuppression despite negative endomyocardial biopsies. We report 2 unusual cases of acute allograft dysfunction that highlight the importance of caution in adopting an empiric strategy of profound immunosuppression in the absence of objective data to support graft rejection.