We have generated B-NDG B2m plus/hIL15 mice, a highly immunodeficient mouse model lacking MHC I and expressing IL-15 for improved NK cell engraftment. ​ B-NDG B2m plus/hIL15 mice have a significantly extended life span, with reduced GvHD upon human PBMC engraftment when compared to B-NDG mice with intact MHC I. ​ Human CD3+ cells and CD56+ cells can be reconstituted successfully from PBMCs in B-NDG B2m plus/hIL15 mice, indicating that B-NDG B2m plus/hIL15 mice are a suitable mouse model for testing novel immunotherapies in the context of human T cell and NK cells.​