Background and purpose. 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. Experimental approach. The effect of FXR activation on aortic plaques formation was assessed by feeding ApoE^-/- mice with the synthetic FXR ligand, INT-747, a cheno-deoxycholic acid derivative, at the dose of 1,3 and 10 mg/kg/day or rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)- ligand, at the dose of 10 mg/kg/day for 12 weeks. Key results. Administration of INT-747 reduced formation of aortic plaque area by 95% (P<0.01) and exerted a similar anti-plaque activity of rosiglitazone. INT-747 administration to ApoE^-/- mice reduced aortic expression of IL-1, IL-6 and CD11b mRNA while upregulates 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 1-c, 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 syntetic ligands in these cell type, attenuated IL-1, IL-6 and TNF- 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- generation by LPS-stimulated macrophages. FXR was also able to reduce CD36 and ABCA1 expression on macrophages. Conclusions and Implications. 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.