Although the porcine organs used for xenotransplantation have been genetically modified to prevent hyperacute rejection and reduce cell- and antibody-mediated rejection, intensive pharmacological immunosuppression is still required to prevent rejection. The expression of an immunosuppressive protein on the surface of the pig transplant could help to prevent rejection. Retroviral transmembrane envelope proteins containing a highly conserved domain, the so-called immunosuppressive (isu) domain, are known to be immunosuppressive. These proteins, including the transmembrane envelope protein p15E of the porcine endogenous retrovirus (PERV), have been shown to inhibit lymphocyte activation in vitro and modulate cytokine release and gene expression as shown by cytokine arrays and microarrays. In vivo studies have shown that expression of various retroviral transmembrane envelope proteins on murine tumor cells, which are otherwise eliminated by the immune system, can enable tumor formation in immunocompetent mice by suppressing host immune responses. In a model experiment, a construct encoding a part of p15E of PERV including the isu domain was transfected into human 293 cells and the expression was analyzed by immunofluorescence and flow cytometry. These cells were subsequently co-cultured with peripheral blood mononuclear cells (PBMCs) from healthy human donors. Although p15E expression on 293 cells was low, co-culture induced human PBMCs to secrete higher levels of IL-10 and to upregulate the expression of IL-6, IFN-α, TNF-α, MMP1, and SEPP1. Additionally, p15E expression led to a downregulation of MHC class I molecules and preliminary data indicate that p15E expression could have a protective effect against cellular cytotoxicity. If the expression of p15E can be significantly increased, the expression of p15E on the surface of porcine xenotransplants could substantially reduce the requirement for systemic immunosuppression. Notably, expression of a transfected p15E construct represents an optimal strategy for such an approach, as p15E is encoded endogenously in all pigs, and pigs are immunologically tolerant to it, not producing antibodies against the protein. The incorporation of the immunosuppressive molecule p15E into pig xenotransplants could represent a significant advancement in the field of transplantation, potentially providing an additional advantage over allotransplantation.