High-fat/high-cholesterol diet (HF) and smoking are risk factors for atherosclerosis and are typical features of a “western society life style”. In order to induce atherosclerosis in the aortic arch, apolipoproteine-deficient (ApoE-/-) mice were fed a HF diet or a normal chow diet for 30 days or fed a normal chow diet and exposed for 5 or 30 days to mainstream smoke (MS) from the University of Kentucky reference cigarette 2R4F. To elucidate the underlying mechanisms of HF- and MS-induced atherosclerosis, the gene expression pattern of the aortic arch was analyzed by DNA microarray and the following were investigated: “acute smoke effect” (5d smoke vs. 5d SHAM), “subchronic smoke effect” (30d smoke vs. 30d SHAM), “subchronic HF effect” (30d HF diet vs. 30d normal chow diet), and “aging effect” (30d SHAM vs. 5d SHAM). Hierarchical clustering and Venn analysis revealed that the different treatment groups showed mainly different sets of differentially expressed genes. Further pathway analysis (ingenuity) showed the unique and significant involvement of 9 pathways in response to MS exposure for 30 days, including pathways relevant in atherogenesis, e.g., nitric oxide signaling and NRF2-mediated oxidative stress response. In response to HF diet, 14 other pathways were detected that are known to play a role in atherogenesis, e.g., NFκB - and GM-CSF-signaling. In addition to these unique pathways, two pathways were shared by both treatments, i.e., PDGF-signaling and purine metabolism. These results indicate that different risk factors induce atherogenesis by different disease mechanisms.