Human lymphoematopoietic stem cells engraft in irradiated immunodeficient mice that are homozygous for the severe combined immunodeficiency (scid) mutation. Engraftment levels in CB-17-scid/scid mice, however, have been low and transient, decreasing the utility of this model for investigation of the development potential and function of human stem cells. In the present study, we have used NOD/LtSz-scid/scid mice as recipients and human cord blood as a source of donor stem cells. Our results demonstrate that NOD/LtSz-scid/scid mice support approximately fivefold higher levels of human stem cell marrow engraftment than do CB-17-scid/scid mice. Human CD34+ cells are present in the marrow of recipient mice, and the engrafted cells readily peripheralize to the circulation of the host. Terminal differentiation of the stem and progenitor cells into mature progeny is limited. Using a multiple-day injection protocol developed in mice, which allows engraftment of stem cells between congenic mice in the absence of irradiation preconditioning, we observed high levels of human cell engraftment in unirradiated NOD/LtSz-scid/scid recipients after three or five consecutive-day injections. These results demonstrate that NOD/LtSz-scid/scid mice support high levels of human stem cell engraftment and that xenogeneic lymphohematopoietic stem cells can engraft in unirradiated hosts without the need for ablative reconditioning. This model will be useful for the in vivo investigation of human stem cells and for the preclinical analysis of human stem cells for transplantation.