Xenotransplantation of human cells into immunodeficient mice has been used to develop models of human haemopoiesis and lymphoid cell function. However, the utility of existing mouse strains can be limited by shortened life‐spans, spontaneous production of functional lymphocytes with ageing, and residual innate immunity leading to variable levels of engraftment. Mice with a deletion of the common cytokine receptor γ chain (γc) gene have reduced numbers of peripheral T and B lymphocytes, and absent natural killer cell (NK) activity. A genetic cross with a recombinase activating gene 2 (RAG2)‐deficient strain produced mice doubly homozygous for the γc and RAG2 null alleles (γc⁻/RAG2⁻). These mice have a stable phenotype characterized by the absence of all T lymphocyte, B lymphocyte and NK cell function. Injection of human B‐lymphoblastoid cells resulted in earlier fatal metastatic lymphoproliferative disease than in NOD/LtSz‐scid controls. This was particularly evident in animals injected intravenously, possibly because of residual NK activity in NOD/LtSz‐scid mice. Levels of engraftment with peripheral‐blood‐derived human lymphocytes were also increased and associated with higher CD4/CD8 ratios. These findings demonstrate that this new strain of immunodeficient mice has significant advantages over existing strains for engraftment of human cells, and may be useful for study of adoptive immunotherapy and novel therapies for GvHD and HIV infection.