OBJECTIVE Circulating leukocytes play a crucial role during arteriogenesis. However, known pro-arteriogenic compounds (MCP-1, GM-CSF) acting via monocytic pathways also exert positive effects on granulocytes and lymphocytes. The role of these two cell types in arteriogenesis remains yet to be clarified, which was the aim of the current study. METHODS Ninety New Zealand White Rabbits received either phosphate buffered saline (PBS), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), neutrophil activating protein-2 (NAP-2) or lymphotactin (Ltn) via osmotic minipumps after unilateral femoral artery ligation. In vitro stimulation and in vivo assessment of chemoattraction confirmed cell-specific action of the compounds in rabbits. Arteriogenesis was evaluated by angiography and collateral conductance measurements using fluorescent microspheres. Quantitative immunohistology was used to quantify transmigrated leukocyte subtypes after infusion of the factors. RESULTS MCP-1 infusion attracts monocytes and granulocytes, whereas IL-8 attracts all three cell types albeit monocytes to a significantly lower degree than MCP-1. NAP-2 and lymphotactin selectively attract granulocytes, respectively, lymphocytes. Of the tested cytokines, only MCP-1 stimulates arteriogenesis, as assessed by collateral conductance measurements ((ml/(min 100 mmHg)): PBS, 50.70+/-5.15; MCP-1, 216.30+/-12.30; IL-8, 58.91+/-5.56; NAP-2, 66.83+/-8.72; Ltn, 52.80+/-5.37) and angiographic findings. CONCLUSIONS This study for the first time provides evidence that not granulocytes or T-lymphocytes but monocytes are the key mediators of arteriogenesis.