A positive pretransplant flow cytometry cross-match (FC-XM) allows precise identification of high-risk recipients vulnerable to hyperacute or accelerated rejection after transplantation. Living donor kidney transplant recipient candidates with positive cross-match have been successfully treated with a combination of plasmapheresis (therapeutic plasma exchange, TPEX) and intravenous immunoglobulin (IVIG), achieving conversion to negative cross-match and successful transplant. We report the first successful case of simultaneous pancreas kidney transplant (SPKT) from a living donor (LD) performed against an initially positive FC-XM, converted to negative using a protocol based on TPEX and IVIG in combination with antiCD20 monoclonal antibody. This strategy of overcoming the cross-match barriers in living donation may offer a chance of successful transplantation to highly sensitized candidates for SPKT, for whom cadaveric transplant is difficult to achieve.