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 (Rag1null) and interleukin (IL)-2 receptor common gamma chain (IL2rγnull), and compare its ability to support lymphohaematopoietic cell engraftment with that achieved in radiosensitive NOD.CB17–Prkdcscid (NOD–Prkdcscid) IL2rγnull mice. We observed that immunodeficient NOD–Rag1null IL2rγnull mice tolerated much higher levels of irradiation conditioning than did NOD–Prkdcscid IL2rγnull 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 Rag1null and scid stocks of immunodeficient NOD mice harbouring the IL2rγnull mutation support similar levels of human lymphohaematopoietic cell engraftment. NOD–Rag1null IL2rγnull mice will be an important new model for human lymphohaematopoietic cell engraftment studies that require radioresistant hosts.