Extra virgin olive oils are rich in monounsaturated fatty acids and minor constituents with antioxidant properties that may influence atherosclerosis development. In this study we assessed the effects of a 10-week high fat high cholesterol diet containing either 20% (w/w) Picual olive oil (n=8) rich in polyphenols, 20% (w/w) Arbequina olive oil (n=8) poor in polyphenols, or 20% (w/w) palm oil (n=8) on plasma lipid and glucose metabolism, aortic root lesion size, hepatic hepatic fat content, and the hepatic proteome in female Apoe-/- mice. Both extra virgin olive oils decreased atherosclerosis (p<0.01), but increased plasma cholesterol levels (p<0.01). Only Picual olive oil lowered plasma triglycerides but increased plasma non-esterified fatty acids (NEFA) levels (both p<0.05). Both olive oils increased hepatic fat content and hepatic adipophilin levels (p<0.05). Proteomics identified a range of antioxidant enzymes that were differentially regulated by olive oil consumption as compared with palm oil consumption. We found a clear association between consumption of extra virgin olive oils and differential regulation of adipophilin and betaine homocysteine methyl transferase as biomarkers of hepatic lipid metabolism in relation to insulin resistance. Principal component analysis revealed that parameters involved in the hepatic steatosis explained most of the treatment effect of the Picual olive oil. In conclusion, a "systems biology" approach provided novel insights into the triglyceride-lowering and anti-atherogenic mechanisms of extra virgin olive oils. The up-regulation of a large array of anti-oxidant enzymes may offer sufficient protection against lesion development and diminish oxidative stress levels instigated by hepatic steatosis.