AbstractThe major barrier to successful discordant xenogeneic organ transplantation is the phenomenon of hyperacute rejection (HAR). Hyperacute rejection results from the deposition of high‐titer preformed antibodies that activate serum complement on the luminal surface of the vascular endothelium, leading to vessel occlusion and graft failure within minutes to hours. Here we describe our strategy to overcome HAR in the pig‐to‐primate transplant setting, which includes the genetic incorporation into transgenic organs and high level expression of both a novel human bifunctional complement inhibitor and a human blood group enzyme. The expression of the human blood group enzyme is designed to reduce significantly the natural antibody reactivity to the discordant pig tissue, whereas expression of the complement inhibitor results in inhibition of complement‐mediated cell activation and lysis. High‐level cell surface expression of the complement inhibitor and high‐level expression of the human blood group enzyme in vascular endothelium effectively eliminate both the antibody and complement components of the massive inflammatory response to the xenogeneic tissue. Elimination of HAR will establish inroads into understanding the cellular immune response toward the discordant tissue. It is conceivable that standard immunosuppressive regimens routinely practiced with allotransplantation can also be effective drug therapies for xenotransplantation. Therefore it is critical to develop a system that tests these possibilities in order to solve an ever‐growing need for donor organs.