Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. A critical regulator of inflammatory processes represents the mitogen-activated protein kinase–activated protein kinase-2 (MK2). Therefore, we investigated the functional role of MK2 in atherogenesis in hypercholesterolemic mice as well as potentially underlying mechanisms in vivo and in vitro. Activation of MK2 (phospho-MK2) was predominantly detected in the endothelium and macrophage-rich plaque areas within aortas of hypercholesterolemic LDL receptor–deficient mice (ldlr^−/−). Systemic MK2 deficiency of hypercholesterolemic ldlr^−/− mice (ldlr^−/−/mk2^−/−) significantly decreased the accumulation of lipids and macrophages in the aorta after feeding an atherogenic diet for 8 and 16 weeks despite a significant increase in proatherogenic plasma lipoproteins compared with ldlr^−/− mice. Deficiency of MK2 significantly decreased oxLDL-induced foam cell formation in vitro, diet-induced foam cell formation in vivo, and expression of scavenger receptor A in primary macrophages. In addition, systemic MK2 deficiency of hypercholesterolemic ldlr^−/− mice significantly decreased the aortic expression of the adhesion molecule VCAM-1 and the chemokine MCP-1, key mediators of macrophage recruitment into the vessel wall. Furthermore, silencing of MK2 in endothelial cells by siRNA reduced the IL-1β–induced expression of VCAM-1 and MCP-1. MK2 critically promotes atherogenesis by fostering foam cell formation and recruitment of monocytes/macrophages into the vessel wall. Therefore, MK2 might represent an attractive novel target for the treatment of atherosclerotic cardiovascular disease.