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A novel immunosuppression protocol using rituximab and plasma exchange treatment was developed for ABO-incompatible living donor liver transplantation (ABO-I LDLT). The aim of this study was to investigate the kinetics of anti-blood type isoagglutinin titers and the number of blood B lymphocytes in ABO-I LDLT with the new protocol and their impact on the outcomes after ABO-I LDLT.Fifteen patients underwent ABO-I LDLT plus splenectomy with the new protocol between November 2005 and December 2010, and their data were retrospectively analyzed.CD19-positive lymphocytes in the blood rapidly disappeared after rituximab treatment and began to recover approximately 6 months later. Anti-blood type isoagglutinin titers were lowered by pretransplant plasma exchange (23∼212→21∼28). Although the anti-donor blood type isoagglutinin titers remained consistently low after transplantation in comparison to the pretreatment levels, they persisted long after LDLT, whereas posttransplant biopsy specimens showed sustained A/B antigens on the graft livers. ABO-I hepatitis C virus-positive patients were prone to acceleration of hepatitis C viremia and cytomegalovirus antigenemia in comparison to the control patients.Although the new protocol for ABO-I LDLT yielded great success with 100% graft survival, the acceptable anti-blood type isoagglutinin titers just before LDLT, and its application to hepatitis C-positive patients must be determined.