We report two cases of ABO-incompatible living-donor kidney transplantation (ABOi KT) performed in patients with exceptionally high ABO antibody titers. Both donor and recipient refused blood transfusions for religious reasons, limiting the use of plasma exchange. The desensitization protocol consisted of plasmapheresis (PP) using albumin solution, rituximab (300 mg), and high-dose intravenous immunoglobulin (IVIg
4 g/kg). Despite aggressive desensitization procedure, ABO antibody titers did not go down to our acceptable upper limit of 1:64
the titer at transplantation was 1:256 in both cases. Given the high risk of acute antibody-mediated rejection (ABMR), the anti-complement C5 component monoclonal antibody (eculizumab
900 mg) was administered prophylactically before graft reperfusion in order to inhibit complement activation. For both cases, postoperative courses were unremarkable, without any rejection episodes over one year. No additional doses of eculizumab were administered post-transplantation. We suggest that ABOi KT may be considered safe once early post-transplant ABMR is suppressed, allowing for immunological accommodation. Furthermore, despite the elevated antibody titers, the prophylaxis with eculizumab successfully inhibited early post-transplant complement activation, protecting kidney transplants from ABMR. These findings support the prophylactic use of eculizumab administration at the time of transplantation in high-risk cases of ABOi KT.