Reduced chimerism occurs in BMT when Anxa2 is blocked during transplantation. Competitive long-term bone marrow transplantations (CLT-BMTs) were used to determine the effect of Anxa2 blockade on HSC engraftment. HSCs isolated on the basis of the SLAM family of receptors (CD150 and CD48) derived from Ly-5.1 (CD45.1) mice using a maximum of 36 HSCs were transplanted into Ly-5.2 (CD45.2) congenic C57BL6 mice along with a mixture of a radioprotective dose of Ly-5.2 cells (2 × 105 cells). Antibody to Anxa2, or a synthetic peptide corresponding to the N-terminal Anxa2 peptide at 10 μg/kg (0.2 μg/animal), or IgG and scrambled peptide controls were used to block Anxa2 activity. Sixteen weeks after transplantation the percentages of marrow cells bearing the Ly-5.2 and Ly-5.1 phenotypes were determined in peripheral blood analyzed by flow cytometry. The data demonstrate that targeting Anxa2 prevents HSC engraftment. Data are representative of 2 independent investigations where *P < .05 versus the control.