In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein a (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In the present study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman), in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages in C57BL/6 with Sirpahuman/human had an affinity for human CD47 significantly stronger than those with SirpaNOD/NOD, and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity to mouse CD47, and BRGShuman mice did not show blood cytopenia that was seen in Sirpa-/- mice. In xenotransplantation, BRGShuman mice showed significantly efficient engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, and improved reconstitution in peripheral tissues, as compared to BRG with SirpaNOD/NOD (BRGSNOD) mice. BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia as well as of subcutaneously transplanted human colon cancer cells as compared to those in BRGSNOD mice. The BRGShuman mouse should be a useful basic line in establishing a more faithful xenotransplantation model to study normal and malignant human stem cells.