The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that functions as an endogenous sensor for bile acids and regulates cholesterol and fatty acid metabolism. The effect of FXR activation on aortic plaque formation was assessed by feeding apolipoprotein E-deficient (ApoE−/−) mice with the synthetic FXR ligand INT-747, a cheno-deoxycholic acid derivative, at doses of 3 and 10 mg·kg−1·day−1, or with rosiglitazone, a peroxisome proliferator-activated receptor-γ ligand, at the dose of 10 mg·kg−1·day−1 for 12 wk. Administration of INT-747 reduced formation of aortic plaque area by 95% ( P < 0.01), and a similar antiplaque activity was exerted by administration of rosiglitazone. INT-747 administration to ApoE−/− mice reduced aortic expression of IL-1β, IL-6, and CD11b mRNA, while it upregulated the expression of FXR and its target gene, the small heterodimer partner (SHP). FXR activation reduced the liver expression of sterol regulatory element binding protein 1c, resulting in reduced triglyceride and cholesterol content in the liver and amelioration of hyperlipidemia. FXR expression, mRNA and protein, was detected in human macrophages and macrophage cell lines. FXR activation by natural and synthetic ligands in these cell types attenuated IL-1β, IL-6, and TNF-α gene induction in response to Toll-like receptor 4 activation by LPS. Using spleen monocytes from wild-type and FXR−/− mice, we demonstrated that FXR gene ablation exacerbates IL-6 and TNF-α generation by LPS-stimulated macrophages. FXR was also able to reduce cholesterol uptake on macrophages by regulation of CD36 and ABCA1 expression. We found that FXR and SHP are expressed in the aorta and macrophages and that FXR ligands might have utility in prevention and treatment of atherosclerotic lesions.