BACKGROUND-: Monocyte activation and migration into the arterial wall are key events in atherogenesis associated with hypercholesterolemia. CD11c/CD18, a β2 integrin expressed on human monocytes and a subset of mouse monocytes, has been shown to play a distinct role in human monocyte adhesion on endothelial cells, but the regulation of CD11c in hypercholesterolemia and its role in atherogenesis are unknown. METHODS AND RESULTS-: Mice genetically deficient in CD11c were generated and crossbred with apolipoprotein E (apoE) mice to generate CD11c/apoE mice. Using flow cytometry, we examined CD11c on blood leukocytes in apoE hypercholesterolemic mice and found that compared with wild-type and apoE mice on a normal diet, apoE mice on a Western high-fat diet had increased CD11c monocytes. Circulating CD11c monocytes from apoE mice fed a high-fat diet exhibited cytoplasmic lipid vacuoles and expressed higher levels of CD11b and CD29. Deficiency of CD11c decreased firm arrest of mouse monocytes on vascular cell adhesion molecule-1 and E-selectin in a shear flow assay, reduced monocyte/macrophage accumulation in atherosclerotic lesions, and decreased atherosclerosis development in apoE mice on a high-fat diet. CONCLUSIONS-: CD11c, which increases on blood monocytes during hypercholesterolemia, plays an important role in monocyte recruitment and atherosclerosis development in an apoE mouse model of hypercholesterolemia. © 2009 American Heart Association, Inc.