Ischemic reperfusion injury (IRI) enhances allograft immunogenicity, worsens transplantation outcome, and is the primary cause of activation of the recipient innate immune response, resulting in subsequent amplification of the alloimmune adaptive response. Here, we aimed at demonstrating that the link between innate injury and alloimmunity occurs predominantly through activation of allograft-derived dendritic cells (ADDC). Perfusion of MCI-186, a free radical scavenger, into donor cardiac allografts prior to transplantation resulted in prolongation of complete MHC-mismatched allograft survival in the absence of immunosuppression (MST of 8 vs. 26 days). This prolongation was associated with a reduction in trafficking of ADDC to recipient lymphoid tissue as well as a reduction in T cell priming. Depleting ADDC with diphtheria toxin (using DTR-GFP-DC mice as donors) 24 h prior to transplant resulted in abrogation of the prolongation observed with MCI-186 treatment, demonstrating that the beneficial effect of MCI-186 is mediated by ADDC. This donor-specific anti-ischemic regimen was also shown to reduce chronic rejection, which represents the primary obstacle to long-term allograft acceptance. These data for the first time establish a basis for donor anti-ischemic strategies, which in the ever-expanding marginal donor pools, can be instituted to promote engraftment.