In the present study, we aimed to examine whether Rb2 can counteract the role of miR-216a in the inflammatory response, macrophages polarization, and lipid phagocytosis in atherosclerotic ApoE−/− mice in vivo and in macrophages or foam cells in vitro, expecting to find a novel therapeutic strategy for atherosclerosis. This evidence concerns the gene RBL2 and atherosclerosis.