A 46-year-old female suffering from liver cirrhosis was referred to us for living-donor liver transplantation (LDLT). Pre-transplant lymphocyte cross-match tests were positive. The recipient showed immunoreactivity against donor human leukocyte antigen (HLA) Class I antigens, a finding confirmed by flow cytometry. Additional tests confirmed donor-specific lymphocyte immunoreactivity against HLA B 55. As no other suitable donor was available, we performed LDLT coupled with splenectomy, despite the positive cross-match. Tacrolimus, methylprednisolone and mycophenolate mofetil were used postoperatively for immunosuppression. The postoperative course was uneventful until Day 3 when blood tests showed disorders in liver function and the patient's condition suddenly worsened. Although intensive care (including plasma exchange) was given, her condition continued to deteriorate. Flow cytometry initially showed that immunoreactivity against Class I antigens was down-regulated immediately after LDLT, but further testing showed that it had increased again. We diagnosed humoral rejection based on clinical, immunological and histopathological findings and suggest that this was mediated by an immune response to donor-specific antigens. The patient experienced multi-organ failure and died on post-operative Day 9.