ApoE−/− mice exhibited markedly reduced lesion sizes throughout atherosclerotic aortas and significantly less advanced lesions. The proportion of Mac3-positive macrophages was higher in plaques from HDAC9 −/− ApoE −/− mice, but this was largely because of a lower proportion of advanced lesions. Analysis of human atherosclerotic plaques revealed no association between rs2107595 and specific plaque characteristics. Conclusions-Our results suggest that HDAC9 represents the disease-relevant gene at the stroke and coronary artery disease risk locus on 7p21.1, and that risk alleles in this region mediate their effects through increased HDAC9 expression. Targeted inhibition of HDAC9 might be a viable strategy to prevent atherosclerosis.