While genetically modified swine organs could resolve shortages in organ transplantation, pre-existing human antibodies that react to and destroy pig cells are the major barrier to xenotransplantation for clinical applications. Studies using simple genetically altered pig donors (α1,3‐galactosyltransferase knockout, hDAF transgenic) combined with an anti‐CD154 (CD4+ T cells) antibody‐based immunosuppression regimen prolonged life‐sustaining kidney xenografts significantly longer in rhesus monkeys than in previous reports. In vitro study results suggested that rhesus CD4+ T cells required the presence of swine leukocyte antigen class II to mount an effective proliferative response. The combination of low pretransplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival.