Approximately 80-85% of D-negative (D-) persons produce anti-D antibodies after exposure to D-positive (D+) red blood cells (RBCs). Previously, anti-D was the most commonly detected Rh antibody, but its incidence has greatly decreased due to the prophylactic use of Rh immunoglobulin (RhIG). Anti-D antibody formation may occur following RhD-incompatible organ transplantation when D- recipients are exposed to D+ RBCs that originate from a donor organ. As a large volume of donor blood may be contained within the transplanted organ, the use of a large amount of RhIG is required in RhD-incompatible liver transplantation. Here, we describe the use of a large amount of RhIG to treat a patient following RhD-incompatible liver transplantation. This patient was a 71-yr-old woman with hepatitis C virus-related liver cirrhosis, who had an A/D- blood type. The donor was her grandson, whose blood type was O/D+. The recipient's preoperative anti-D antibody test was negative. One unit of O/D- irradiated leukoreduced RBCs and three units of A/D- fresh frozen plasma were transfused during liver transplantation. An equal amount (12,000 IU) of RhIG was infused intravenously, immediately after liver transplantation and a second time on post-operation day 1. The anti-D titer was 1:64 on the first post-operation day, and had increased to 1:128 by the following day. By 1 month after the surgery, the titer had decreased to 1:4. In this case of liver transplantation, RhIG was actively used to prevent RhD sensitization and the subsequent occurrence of adverse events associated with RhD-incompatible liver transplantation.