Macrophage-derived foam cells are critical components of atherosclerotic lesions and the ways in which the inflammatory response of foam cells influences atherogenesis is of great interest. Previously we demonstrated that interferon-beta (IFN-β) promotes atherogenesis. But how IFN-β influences foam cell formation and inflammation is not understood yet. Hence, we assessed the functional involvement of IFN-β in these processes in a normal versus high cholesterol environment. First, we performed a microarray study on IFN-β-stimulated bone marrow-derived macrophages (BMDMS) under normocholesterolemic conditions, which showed upregulation of immune response pathways and downregulation of cholesterol biosynthesis. Secondly, we loaded BMDMs with acLDL followed by 6h IFN-β treatment, which surprisingly impaired the induction of IFN-β target genes, like CCL5 and CXCL10. To validate these findings in vivo, LDLR^-/- mice were put on normal chow (NC) or a high cholesterol diet (HCD) for 10 weeks. Peritoneal macrophages (PEMs) were collected 4 days after intraperitoneal thioglycolate administration, combined with IFN-β (5000 U/ml) or PBS administration 24 and 8 hours before sacrifice. Lipid loading increased following IFN-β treatment, accompanied by increased scavenger receptor-A (SR-A) gene expression. This lipid loading also resulted in PEM IFN-β-hyporesponsiveness, since several IFN-β target genes were again less expressed compared to NC PEMs. In addition, ex vivo culturing of PEMs from IFN-β-treated animals on HCD versus NC showed an overall decreased inflammatory activity, as gene expression of inflammatory markers was reduced and secretion of IL-6, TNF and NO was decreased. Currently we assess how HCD interferes with IFN-β-induced effects by investigating the IFN-β-induced activation of transcription factors like STAT1, IRF3 and IRF9 in control and acLDL loaded BMDMs. Altogether, IFN-β promotes foam cell formation, possibly by increased lipid influx via SR-A. Interestingly, increased lipid loading results in hyporesponsiveness to IFN-β. More research is needed to reveal the biological relevance for this hypercholesterolemia-induced hyporesponsive state.