ABO-incompatible liver transplants (LTX) have been associated with a high risk of antibody-mediated rejection, poor patient and graft survival, and a high risk of vascular thrombosis and ischemic bile duct complications. We used pretransplantation and posttransplantation double-volume total plasma exchange (TPE), splenectomy, and quadruple immunosuppression (cyclophosphamide or mycophenolate mofetil, prednisone, cyclosporine or tacrolimus, and OKT3 induction) in 14 patients receiving ABO-incompatible LTX between June 1992 and February 2001: A(1) to O (seven), B to O (two), B to A (two), A to B (one), AB to A (one), and AB to O (one). Actuarial 1- and 5-year patient and graft survival rates are 71.4% and 61.2 % and 71.4% and 61.2%, respectively, with a mean follow-up of 62.9 +/- 39.4 months. Ten acute cellular rejections occurred, and the mean time to the first episode was 62 +/- 33 days. All were steroid sensitive. No antibody-mediated rejection or vascular thromboses occurred. Pretransplantation pre-TPE immunoglobulin (Ig) G mean isohemagglutinin titers were 262 +/- 326, compared with pretransplantation post-TPE titers of 65 +/- 103 (P =.04). Eight of nine patients with measurable titers before and after TPE achieved a reduction in titers. The mean number of posttransplantation TPE was 5.5 +/- 4.1 (range, 0 to 12), and the last TPE was on postoperative day 9.4 +/- 5.3. IgG isohemagglutinin titers 2 weeks posttransplantation had increased to 153 +/- 309 (P =.03 compared with pretransplantation pre-TPE IgG). ABO-incompatible liver transplantations can be performed with acceptable patient and graft survival rates with a low risk of antibody-mediated rejection with a combination of TPE, splenectomy, and quadruple immunosuppression. Recovery of isohemagglutinin antibody levels without humoral rejection suggests that accommodation may be the protective mechanism preventing late antibody-mediated rejection.