Heart graft arteriosclerosis remains a severe and irreversible complication of allogeneic heart transplantation despite prophylactic therapy. Immunologically mediated endothelial damage was proposed as a stimulus for the development of graft arteriosclerosis. The vascular lesions may accumulate large amounts of lipid resembling atheromas or may be purely proliferative, as illustrated in the case of a 42 yr old heart transplant patient who developed slowly progressive graft dysfunction at 8 mo. posttransplantation. Endomyocardial biopsy 10 mo. posttransplantation revealed proliferative arteriolar occlusion, while changes on the coronary angiogram were minimal. Repeat biopsy at 11 mo. showed ischemic myocardial necrosis. The patient expired shortly thereafter. On postmortem examination, proliferative graft arteriosclerosis affecting both intramural and epicardial vessels was present, along with massive biventricular infarction. Tissue immunofluorescence studies demonstrated extensive vascular deposition of immunoglobulin and complement. The presence of proliferative arteriolar occlusion on endomyocardial biopsy is predictive of poor heart graft survival; proliferative graft arteriosclerosis may appear as advanced small vessel disease before extensive large vessel involvement is detected by coronary angiogram; and immunofluorescence results support an immune-mediated mechanism of vascular injury in proliferative heart graft arteriosclerosis.