Significance Atherosclerosis is an inflammatory condition of the artery wall and main cause of myocardial infarction and stroke. Inflammatory processes evoking atherogenic lesions involve NF‐κB–dependent endothelial-cell activation and monocyte/macrophage recruitment. Constitutive photomorphogenesis 9 (COP9) signalosome (CSN) subunit 5 (CSN5) and the CSN control cullin/RING E3 ligase-dependent degradation of cell-cycle regulators and inhibitor of κB‐α by cleaving neural precursor cell-expressed, developmentally down-regulated-8 (NEDD8) from cullins. CSN5 promotes tumorigenesis in humans. We generated a conditional KO mouse in which macrophage/granulocyte-CSN5 is deleted. We show that CSN5 suppresses macrophage inflammation and that mice lacking myeloid CSN5 develop larger atherosclerotic lesions. The NEDDylation inhibitor MLN4924 attenuates early atherosclerosis and inhibits inflammation in macrophages and endothelial cells. With MLN4924 in clinical trials, deNEDDylation approaches may qualify as therapeutics to reduce early-stage atherogenesis.