We reported that complement (C) becomes activated and cleaved in bone marrow during preconditioning for hematopoietic transplantation and the third C component (C3) cleavage fragments, C3a and desArg C3a, increase responsiveness of hematopoietic stem/progenitor cells (HSPCs) to stromal-derived factor-1 (SDF-1). We also showed that this homing-promoting effect is not C3a receptor (C3aR) dependent. Herein, we report our new observation that transplantation of C3aR−/− HSPCs into lethally irradiated recipients results in:(1)∼ 5–7 day delay in recovery of platelets and leukocytes;(2) decrease in formation of day 12 colony-forming units-spleen; and (3) decrease in the number of donor-derived CFU-granulocyte-macrophage progenitors detectable in the bone marrow cavities at day 16 after transplantation. In agreement with the murine data, blockage of C3aR on human umbilical cord blood CD34+ cells by C3aR antagonist SB290157 impairs their engraftment in non-obese diabetic/severe combined immunodeficient mice. However, HSPCs from C3aR−/− mice stimulated by C3a still better responded to SDF-1 gradient, after exposure to C3a, they secrete less matrix metalloprotease-9 and show impaired adhesion to stroma cells. We conclude that C3a, in addition to enhancing responsiveness of HSPCs to SDF-1 gradient in a C3aR independent manner, may also directly modulate HSPC homing by augmenting C3aR-mediated secretion of matrix metalloprotease-9 and cell adhesion.