Not all patients with complement deposition of the heart have developed hemodynamic instability at the time of diagnosis, suggesting that immunoprotective mechanisms reside within grafts. We hypothesized that decay-accelerating factor (DAF) could provide a first-line defense against complement injury, thus explaining the discrepancy in hemodynamics. Thus, we examined the role of DAF in the clinical presentation of antibody-mediated cardiac allograft rejection. Endomyocardial biopsies from C4d(+)/C3d(+) patients were immunoflourescently stained for DAF, and its expression was compared in patients who did (n = 5) and did not (n = 4) exhibit allograft dysfunction. Endomyocardial biopsies of patients without allograft dysfunction displayed intense staining of endothelial bound DAF expression at the time of antibody-mediated cardiac allograft rejection. Conversely, biopsies of patients with allograft dysfunction showed no evidence of DAF at that time. Expression of DAF on cardiac allografts may provide an immunoprotective mechanism against the deleterious effects of complement deposition in patients with antibody-mediated cardiac allograft rejection.