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Atherosclerosis, the major risk factor for cardiovascular disease and the leading cause of death worldwide, is a multifactorial chronic inflammatory disease. Deletion of CD200 in vivo increases myeloid cell numbers and activation resulting in enhanced susceptibility to autoimmune diseases and infection. However, the importance of CD200 in atherosclerosis development is still unknown. To understand the role of CD200 signalling, both the effect of CD200 deletion and provision were assessed in a murine model of atherosclerosis. Firstly, the role of CD200R ligation was examined in a murine model of carotid injury. Apolipoprotein E deficient (ApoE -/-) mice underwent surgery for placement of a perivascular collar and were treated with 10mg/kg of a CD200-Fc fusion protein. Three weeks post injury, carotid arteries were removed and neointima formation was assessed. CD200-Fc fusion protein treatment attenuated neointima development and increased M2 anti-inflammatory macrophage accumulation. Secondly, CD200-deficient (CD200-/-) mice were crossed with ApoE-/- mice. CD200 deficiency accelerated advanced atherosclerotic lesion formation in the aortic roots, as shown by the morphometric measurement of aortic root atherosclerotic lesion development. Moreover, CD200 regulated hypercholesterolemia-induced monocytosis, as its deletion increased the numbers of CCR2-expressing Ly6Chi monocytes in the blood and in the plaques. To further understand the mechanism of CD200-mediated monocytosis in the plaques, the role of the haematopoietic system was assessed by flow cytometry and in vitro culture systems. CD200 deficiency was shown to regulate GM-CSF-mediated myelopoiesis. CD200 does not only affect myeloid cells in the blood, but also in the spleen and in the aorta. In the plaques, CD200 deficiency skewed the phenotype of macrophages towards iNOS+CD86+MHCII+ inflammatory macrophages and enhanced CD4+ T cell activation. Therefore, CD200 regulates macrophage phenotypes and possibly their antigen presenting abilities at advanced stages of atherosclerosis. Finally, a highly multiparametric technique (CyTOF) enabled the detection of CD200 predominantly in stromal cells in the plaques suggesting a key role for stromal-immune cell interactions in CD200-mediated athero-protection. Collectively, these findings identify a new role for CD200 expression in modulating myeloid cell function and phenotype in advanced stages of atherosclerosis.