Lipid deposition in artery walls is implied in the pathogenesis of atherosclerosis and imbalance between uptake and efflux of cholesterol favors the deposition. We investigated the effect of vitamin E with the same dose and duration on the different stages of atherosclerosis in Apolipoprotein E knockout (ApoE KO) mice and explored the potential mechanisms. The results showed that the ApoE KO mouse spontaneously develops atherosclerosis in an age-dependent manner from 14 to 46 weeks on the regular chow. Vitamin E (100 mg/kg) supplementation to ApoE KO mice at 6, 14, and 22 weeks for 8 weeks significantly reduced the atherosclerotic lesion area by 41, 29 and 19% respectively compared to the age-matched control mice; however had no significant effect on the lesion when given at 30 and 38 weeks. In addition, vitamin E supplemented at the ages from 6 to 30 weeks decreased the contents of serum oxLDL and TBARS without affecting the TC and TAG contents in serum and liver. Furthermore, vitamin E supplemented at 6, 14 and 22 weeks down-regulated vasculature mRNA expressions of scavenger receptor CD36 and up-regulated mRNA expressions of PPARγ, LXRα and ABCA1 which are involved in reverse cholesterol transportation; however had no significant effects on these genes when given at 30 and 38 weeks. In conclusion, vitamin E with same dose and duration inhibits the early but not advanced atherosclerotic lesion in ApoE KO mice by anti-oxidation and regulation of mRNA expression of genes involved in cholesterol uptake and efflux, which favors the improvement of atherosclerosis.