IgG Fc receptors (FcγRs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E–deficient mice (apoE^−/−) with FcγR γ chain–deficient mice (γ^−/−). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE^−/− control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49±6% and 56±8%, respectively, compared with the content in apoE^−/− lesions. Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activated Normal T-cell Expressed and Secreted), and intercellular adhesion molecule-1 (ICAM-1) and the activation of nuclear factor-κB (NF-κB) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both γ^−/− and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-κB activation. ApoE^−/− mice have higher levels of activating FcγRI and FcγRIIIA, and inhibitory FcγRIIB, compared with wild-type mice. The DKO mice express only the inhibitory FcγRIIB receptor. We conclude that FcγR deficiency limits development and progression of atherosclerosis. In addition to leukocytes, FcγR activation in VSMCs contributes to the inflammatory process, in part, by regulating chemokine expression and leukocyte invasion of the vessel wall. These results underscore the critical role of FcγRs in atherogenesis and support the use of immunotherapy in the treatment of this disease.