Despite techniques to deplete red cells from major ABO-incompatible allogeneic bone marrow (BM) or to remove recipient isohemagglutinins (IHGs) before transplantation, delayed erythropoiesis and hemolysis, red cell aplasia, and increased red cell transfusion requirements may occur. Twenty-nine recipients of major ABO-incompatible allografts received donor-type frozen fresh plasma (FFP) infusions twice daily to adsorb IHGs in vivo. Engraftment and transfusion requirements were compared between the 29 FFP-treated major ABO-incompatible allograft recipients, 5 recipients of major ABO-incompatible BM who did not receive FFP infusions, 35 recipients of minor ABO-incompatible BM, and 172 recipients of ABO-compatible BM. No significant differences in either transfusion requirements or engraftment were seen in the FFP-treated major ABO-incompatible vs. minor ABO-incompatible or ABO-compatible groups (p values > or = 0.10). The infusion of donor-type FFP represents a simple, effective treatment strategy to neutralize IHGs and to prevent adverse consequences of major ABO incompatibility in the setting of allogeneic BM transplantation. The role of this strategy in the care of patients receiving ABO-incompatible solid organs remains to be defined.