Humanized mice are valuable preclinical models for immuno-oncology research because they allow modeling of human immune cells and human tumors in vivo. Myeloid cells are highly abundant in many tumors and have been associated with tumor progression, metastasis, and therapy resistance. Next-generation humanized mice have been generated to improve the development, diversity, and function of human myeloid cells. In this study, we analyzed human immune cell development and myeloid cell composition in NSG-Quad and MISTRG-6 mice. NSG-Quad mice supported the development of tissue-resident and tumor-infiltrating human macrophages at levels almost comparable to those of MISTRG-6 mice. However, the development of human CD4(+) and CD8(+) T cells was impaired in the blood and spleen but not in the tumor of NSG-Quad mice. In a subset of NSG-Quad mice, human monocytes exhibited increased cellular granularity and elevated expression of activation and checkpoint molecules, consistent with a monocyte hyperactivation syndrome. Our study provides a comprehensive comparative analysis of the frequency and characteristics of circulating, tissue-resident, and tumor-infiltrating myeloid cell populations in NSG-Quad and MISTRG-6 mice, which is key to accurately design and interpret human tumor xenograft studies, particularly with regard to faithful reconstruction of the human tumor-immune microenvironment and preclinical testing.