Immunodeficient hosts engrafted with human lymphohaematopoietic cells hold great promise as a preclinical bridge for understanding human haematopoiesis and immunity. We now describe a new immunodeficient radioresistant non-obese diabetic mice (NOD) stock based on targeted mutations in the recombination activating gene-1 (Rag1^null) and interleukin (IL)-2 receptor common gamma chain (IL2rγ^null), and compare its ability to support lymphohaematopoietic cell engraftment with that achieved in radiosensitive NOD.CB17–Prkdc^scid (NOD–Prkdc^scid) IL2rγ^null mice. We observed that immunodeficient NOD–Rag1^null IL2rγ^null mice tolerated much higher levels of irradiation conditioning than did NOD–Prkdc^scid IL2rγ^null mice. High levels of human cord blood stem cell engraftment were observed in both stocks of irradiation-conditioned adult mice, leading to multi-lineage haematopoietic cell populations and a complete repertoire of human immune cells, including human T cells. Human peripheral blood mononuclear cells also engrafted at high levels in unconditioned adult mice of each stock. These data document that Rag1^null and scid stocks of immunodeficient NOD mice harbouring the IL2rγ^null mutation support similar levels of human lymphohaematopoietic cell engraftment. NOD–Rag1^null IL2rγ^null mice will be an important new model for human lymphohaematopoietic cell engraftment studies that require radioresistant hosts.