Human CD34(+) hematopoietic stem and progenitor cells (HSPCs) can reconstitute a human hemato-lymphoid system when transplanted into immunocompromised mice. While fetal liver- and cord blood-derived CD34(+) cells lead to high engraftment levels, engraftment of mobilized, adult donor-derived CD34(+) cells has remained poor. We generated so-called MSTRG and MISTRG hu-manized mice on a Rag2(-/-)Il2rg(-/-) background carrying a transgene for human SIRPα and human homologues of the cytokines macrophage-colony stimulating factor, thrombopoietin, with or without interleukin-3 and granulocyte-macrophage colony stimulating factor under murine promotors. Here we transplanted mobilized peripheral blood CD34(+) cells in sub-lethally irradiated newborn and adult recipients. Human hematopoietic engraftment levels were significantly higher in bone marrow, spleen and peripheral blood in newborn transplanted MSTRG/MISTRG as compared to non-obese diabetic/severe combined immunodeficient Il2rg(-/-) or human SIRPα-transgenic Rag2(-/-)Il2rg(-/-) recipients. Furthermore newborn transplanted MSTRG/MISTRG mice supported higher engraftment levels of human phenotypically defined HSPCs in bone marrow, T-cells in the thymus, and myeloid cells in non-hematopoietic organs such as liver, lung, colon and skin, approximating the levels in the human system. Similar results were obtained in adult recipient mice. Thus, human cytokine knock-in mice might open new avenues for personalized studies of human (patho)physiology of the hematopoietic and immune system in vivo.