Technical Abstract: Blueberries (BB) contain high levels of polyphenols and exhibit high antioxidant capacity. In this study, protective effects of BB against atherosclerosis and possible underlying mechanisms in reducing oxidative stress were examined in ApoE deficient (apoE-/-) mice. ApoE-/- mice were fed AIN-93G diet (CD) or CD formulated to contain 1% freeze-dried whole BB (BB). The mean lesion areas for ApoE-/- mice fed BB were reduced by 39% (P <0.001) in aorta sinus and 58% (P<0.001) in descending aorta compared to CD fed animals. These anti-atherogenic effects were independent of the serum lipid profile or total antioxidant capacity (as measured by ORAC). Biomarker of lipid peroxidation, F2-isoprostane, was found to be significantly lower in liver of BB fed mice (P<0.05). Gene expressions analyzed by RT-PCR array showed 4 major antioxidant enzymes in aorta (superoxide dismutase 1, superoxide dismutase 2, glutathione reductase, and thioredoxin reductase 1) was up-regulated in BB fed animals. Enzyme activities of superoxide dismutase and glutathione reductase were increased (P<0.05) in liver and/or serum of BB fed mice. In addition, serum paraoxonase 1 activities in serum of BB fed mice were also found to be higher than that in CD fed mice (P<0.05). These data indicate that a strong protective effectiveness of BB against atherosclerosis in apoE-/- mouse model and suggest that the mechanisms may involve reduction in oxidative stress by both inhibition of lipid peroxidation and enhancement of antioxidant defense.