Humoral rejection (HR) of the cardiac allograft is neither well characterized nor universally recognized in the transplant/pathology-related literature. One reason for this is that the histologic light-microscopic features are inconsistent, making HR difficult to recognize in the majority of cases. We report an unusual case of cardiac allograft rejection in a patient with a complicated postoperative course who ultimately died within 6 months of transplant. Premortem, HR was not diagnosed in multiple cardiac biopsies. The autopsy revealed unequivocal histologic and immunohistochemical evidence of HR. Vascular distension and endocardial infiltration by numerous macrophages were noted only in the cardiac allograft and were notably absent in the native tissue present within the anastomotic sites. There was capillary deposition of immunoglobulin and complement shown by immunofluorescence staining of frozen tissue, and there was diffuse immunohistochemical staining for C4d within the intramyocardial vessels. This case appears to represent an exaggerated antibody-mediated rejection of the cardiac allograft.