Antibody-mediated rejection (AMR) is a barrier to successful long-term xenograft survival. We compared AMR in kidney xenotransplantation to sensitized kidney allotransplantation in a NHP model. With conventional CNI- based immunosuppressive maintenance, both groups showed limited graft survival with strong AMR features such as interstitial hemorrhage, thrombotic microangiopathy, peritubular capillaritis, and glomerulitis without T cell mediated rejection. The strong similarity between sensitized allo- and unsensitized xeno-rejection suggests a possible common mechanism of rejection in xeno- and sensitized allotransplantation. Currently pig to primate graft survival has markedly improved with interruption of the CD28/B7 and CD40/CD154 costimulation pathways. In theory, the same regimen should control the immune response against xenografts in allosensitized animals. Therefore, further investigation is warranted to evaluate the current successful costimulation blockade-based regimen that has shown great efficacy in xenotransplantation to determine if this strategy may apply as well to sensitized recipients.