Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2K b , I-A b) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2K d , I-A d) or third-party (C3H, H2K k , I-A k) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b + Gr1 + MDSC population was observed in the group treated with donorderived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b + Gr1 + MDScs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient's endogenous MDSCs. Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. The Scientific Registry of Transplant Recipients (SRTR) reported that 14,313 kidney 1 , 7,483 liver 2 , 2,465 lung 3 , 432 heart 4 , 80 pancreas 5 , and 109 intestinal 6 transplants were performed in 2017 in the US (Feb 2019 updated). Nevertheless, number of challenges remain for organ recipients after the transplantation, as they suffer from acute and chronic rejection as well as complications of immunosuppression 7-9. One of the more critical issues pertains to the current state of standard immunosuppressive protocols. Calcineurin inhibitor (CNI) based immunosuppressive protocols are not designed to promote antigen-specific tolerance, and may exacerbate chronic allograft injury (i.e. calcineurin toxicity) 10. Therefore, there is an urgent need to establish safer anti-rejection strategies by targeting antigenspecific alloimmunity.