Macrophage-mediated inflammation is central to atherogenesis. We have determined previously that the CXC chemokine receptor CXCR2 is involved in advanced atherosclerosis. We sought to determine whether one of the ligands of CXCR2, KC/GRO-alpha, can also modulate atherogenesis. KC/GRO-alpha(-/-) mice were generated and mated with the atherosclerosis-prone LDLR(-/-) mice. There was a significant reduction in atherosclerosis in mice lacking KC/GRO-alpha; however, this reduction was only approximately half that seen previously in mice lacking CXCR2 in the leukocyte. To determine whether CXCR2 is involved in the early formation of atherosclerosis, leukocyte-specific CXCR2(-/-) chimeric mice on LDLR(-/-) background were generated. Early fatty streak lesion formation in these mice was not affected by leukocyte CXCR2 deficiency whereas lesions were less developed in mice lacking leukocyte CXCR2 when atherosclerosis was allowed to progress to the intermediate stage. Macrophages were relatively sparse in the lesions of leukocyte CXCR2(-/-) mice despite robust MCP-1 expression. These studies indicate that KC/GRO-alpha/CXCR2 does not play a critical role in recruitment of macrophages into early atherosclerotic lesions but both arterial KC/GRO-alpha and leukocyte-specific CXCR2 expression are central to macrophage accumulation in established fatty streak lesions.