BACKGROUND Hematopoietic stem and progenitor cell (HPC) motility is essential for HPC transplantation. The chemokine CXCL12 is key for HPC motility. Further regulators are of interest to improve HPC transplantation and regenerative medicine. Here the impact of the human chemokine CCL15 on HPC motility was investigated. METHODS CCL15 plasma concentrations were determined during HPC mobilization in humans. Activity of CCL15 on HPCs was investigated in murine assays, including chemotaxis, adhesion, and CFU-A assays, and competitive repopulation assays. RESULTS During HPC mobilization with granulocyte colony-stimulating factor, blood plasma contains increased concentrations (1.1 ± 0.1 ng/ml) of activated CCL15(27-92) versus 0.4 ± 0.1 ng/ml in controls (p = 0.02). CCL15(27-92) significantly enhanced CXCL12-induced transwell migration of Lin-/Sca1+ HPCs and strengthened shear stress-dependent adhesion to vascular cell adhesion molecule-1 (VCAM-1). CCL15(27-92) dose-dependently reduced the colony size in CFU-A assays performed with murine bone marrow and Lin-/Sca1+ HPCs. CCL15(27-92) did not show a direct impact on cell cycle status of HPCs. In murine repopulation assays, pretreatment of bone marrow with CCL15(27-92) significantly increased competitive repopulation. CONCLUSIONS Our results point to a regulation of HPCs by CCL15 by modulating migratory and adhesive properties of HPCs with the potency to improve HPC short-term engraftment in stem cell transplantation.