AbstractRecently, evidence was presented that natural antibodies (NAb) are a crucial barrier to human cellular engraftment in severely immunosuppressed normal mice(Eur. J. Immunol. 1992.22:197.). In this report we show that normal mouse serum contains low titers of NAb against human cells of blood groups type O (H) and B and high titers against human cells of blood group A. Accordingly, human peripheral blood leukocytes (PBL) of group O (H) and B donors could be grafted successfully into normal BCBA mice (H‐2h/k) following irradiation with high dose total body irradiation (TBI). PBL of blood group type A donors did not engraft in normal mice but could be transplanted without difficulty in B cell‐deficient CBA/N mice which lack NAb, after conditioning with high dose TBI. Treatment of lethally irradiated normal BCBA mice with cobra venom factor (COF), which eliminates the third factor of complement, and liposomes containing dichloromethylene diphosphonate (C12DMP), which eliminates macrophages, resulted in engraftment of human blood group type A PBL. This implies that the NAb barrier for discordant xenogeneic cell transplantation can be abrogated.A method utilizing directly labeled probes and flow cytometry is described for the quantitation in mouse serum of NAb, reacting with human cells. Using sera of H‐2b/kmice we show that murine NAb react with human stem cells, granulocytes, lymphocytes and monocytes of blood group A and only weakly with similiar cells from blood group O (H) and B donors. Sera of H‐2b, H‐2dand H‐2kmice of different ages and microflora possess NAb against human erythrocytes of blood group type A and occasionally demonstrate weak titers against erythrocytes of blood groups B and O (H) and the Rh