Surveillance endomyocardial biopsies are a safe, effective way to monitor transplant patients for rejection. In the early post-transplant period, the differential diagnosis of biopsy findings is challenging because of histologic changes possibly related to donor heart dysfunctionor prolonged ischemic times as well as acute rejection. The authors present a case illustrating the diagnostic challenges. The differential diagnosis includes acute humorally mediated rejection, which is a common cause of early allogaft dysfunction. The diagnostic features and significance of humorally mediated rejection and other differential diagnostic entities are described and discussed.