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Humanized mouse models enable the study of human hematopoietic stem cell (HSC) function in vivo. However, human HSC engraftment and self-renewal are still hampered in xenotransplantation settings restricting the study of mechanisms regulating human HSC function. Further, irradiation conditioning limits the study of interactions between human HSCs and niche cells. We previously described NOD/SCID Il2rg-/- KitW41/W41 (NSGW41) mice, which combine an impaired endogenous HSC compartment, due to a loss-of-function KIT receptor, with immunodeficiency and support stable long-term engraftment of human HSCs without the need for preconditioning. By transplanting titrated numbers of human HSCs in primary and secondary recipients, we could show enhanced pick-up, maintenance and expansion of human HSCs in vivo compared to KIT-proficient NSG mice. Thus, human HSCs efficiently engraft in NSGW41 mice whereupon their self-renewal capacity und functionality are conserved. We hypothesized that human KIT-proficient HSCs have a competitive advantage over murine KIT-deficient HSCs and thus can stably engraft in NSGW41 mice. In fact, the endogenous HSC pool is significantly decreased in NSGW41 mice after engraftment of human HSCs, indicating that endogenous HSCs are replaced from their niche. The remaining murine KitW41/W41 HSCs express wildtype levels of KIT receptor, suggesting competition between endogenous and human donor HSCs for the KIT-ligand stem cell factor (SCF). Importantly, analysis of the murine bone marrow niche revealed a significant expansion of CD51+ PDGFRα+ mesenchymal stromal cells (MSCs) upon engraftment of human cells. The transcriptional profile of murine MSCs is significantly altered after humanization. We suggest that human HSCs actively modify the murine bone marrow niche after xenotransplantation and that MSCs provide part of the niche for human HSCs in mice.