Abstract Background 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. Methods and Results To understand the role of CD200 signalling, both the effect of CD200 deletion and provision were assessed in a murine model of atherosclerosis. Firstly, CD200 deficiency in hypercholestorelemic apolipoprotein E deficient (ApoE−/−) mice accelerates advanced atherosclerotic lesion formation in the aortic roots. Moreover, APOE−/− CD200−/− mice exhibit significant increase in specific myeloid cell populations in spleen, blood and aorta. Secondly, the role of CD200R ligation has been examined in a murine model of carotid injury. ApoE−/− mice underwent surgery for placement of a perivascular collar and were treated with 10mg/kg of a CD200-Fc fusion protein. CD200-Fc fusion protein treatment attenuates neointima development and, interestingly, affects macrophage accumulation and polarization. Conclusions Our data indicate that CD200 is an important modulator of myeloid cell function and phenotype in atherosclerosis and suggest that targeting the CD200-CD200R pathway holds promise as a potential therapeutic strategy in atherosclerosis.