Although donor-specific lymphocytotoxic antibodies are regarded as a contraindication for kidney transplantation (KTx), the data available for liver or combined liver or kidney transplantation (cLKTx) are scarce. Here, we report a case of a highly sensitized young man receiving his sixth liver and second kidney graft. Multiple anti-HLA antibodies were present at the time of transplantation. As a result of suspected antibody-mediated graft damage, the patient was treated with rituximab, plasmapheresis, intravenous immunoglobulins, splenectomy, and bortezomib to decrease the antibody production. So far, patient and allograft survival has reached 4 years despite failure to achieve a permanent reduction of anti-HLA antibodies, and particularly nondonor directed antibodies.