The kinetics of isoagglutinin titers and lymphocyte subpopulations including B, T, and natural killer (NK) cells after ABO incompatible (ABO-I) living donor liver transplantation (LDLT) have not been evaluated.From January 2012 to July 2013, consecutive ABO-I LDLT patients were enrolled at the National Cancer Center. Our desensitizing protocol included rituximab, plasma exchanges, basiliximab, and intravenous immune globulin without splenectomy.Twenty patients (14 males, 6 females) underwent ABO-I LDLT due to HCC (n=15) or liver cirrhosis (n=5). There was no hyperacute and antibody-mediated rejection. The isoagglutinin titers were effectively lowered less than 1:16 before operation. CD 19+ B cells were rapidly eliminated after rituximab and suppressed during 6months postoperatively. CD3+ and CD4+ T cells were elevated higher than CD8+ T cells. CD4/CD8 ratio was increased during first 1month postoperatively and decreased thereafter. CD16+CD56+ NK cells were lowered and restored after 4months of LDLT. Among 15 patients with HCC, 5 patients (33.3%) experienced early tumor recurrence (1/8 within Milan and 4/7 beyond Milan).Our protocol showed effective results in preventing antibody-mediated rejection and suppressing B lymphocytes. Application to advanced hepatocellular carcinoma should be considered due to decreased natural immunity after ABO-I LDLT.