To establish a more appropriate animal recipient for xenotransplantation, NOD/SCID/γ mice double homozygous for the severe combined immunodeficiency (SCID) mutation and interleukin-2Rγ (IL-2Rγ) allelic mutation (γ) were generated by 8 backcross matings of C57BL/6J-γ mice and NOD/Shi-scidmice. When human CD34⁺ cells from umbilical cord blood were transplanted into this strain, the engraftment rate in the peripheral circulation, spleen, and bone marrow were significantly higher than that in NOD/Shi-scid mice treated with anti-asialo GM1 antibody or in the β2-microglobulin–deficient NOD/LtSz-scid (NOD/SCID/β2m^null) mice, which were as completely defective in NK cell activity as NOD/SCID/γ mice. The same high engraftment rate of human mature cells was observed in ascites when peripheral blood mononuclear cells were intraperitoneally transferred. In addition to the high engraftment rate, multilineage cell differentiation was also observed. Further, even 1 × 10² CD34⁺ cells could grow and differentiate in this strain. These results suggest that NOD/SCID/γ mice were superior animal recipients for xenotransplantation and were especially valuable for human stem cell assay. To elucidate the mechanisms involved in the superior engraftment rate in NOD/SCID/γ mice, cytokine production of spleen cells stimulated with Listeria monocytogenesantigens was compared among these 3 strains of mice. The interferon-γ production from dendritic cells from the NOD/SCID/γ mouse spleen was significantly suppressed in comparison with findings in 2 other strains of mice. It is suggested that multiple immunological dysfunctions, including cytokine production capability, in addition to functional incompetence of T, B, and NK cells, may lead to the high engraftment levels of xenograft in NOD/SCID/γ mice.