α-Tocopheryl phosphate (TP) is a naturally occurring form of vitamin E found in the body. In the present study we compared the ability of an α-TP mixture (TPM) against a standard vitamin E supplement, α-tocopherol acetate (TA) on the development of atherosclerotic lesions in ApoE-deficient mice. Mice were maintained on either a normal chow diet for 24 weeks (Normal Diet), vs a group in which the final 8 weeks of the 24-week period mice were placed on a high fat (21%), high cholesterol (0.15%) challenge diet (HFHC), to exacerbate atherosclerotic lesion development.. The difference in these two control groups established the extent of the diet-induced atherosclerotic lesion development. Mice in the various treatment groups received either TA (300 mg/kg chow) or TPM (6.7-200 mg/kg chow) for 24 weeks, with TPM treatment resulting in dose-dependent significant reductions in atherosclerotic lesion formation and plasma levels of pro-inflammatory cytokines. TA-treated mice, with the tocopherol equivalent TPM dose (200 mg/kg chow), showed no significant reduction in plasma lipid levels or evidence for aortic lesion regression. At this TPM equivalent TA dose, a 44% reduction in aortic lesion formation was observed. In addition, these TPM treated mice, also showed a marked reduction in aortic superoxide formation and decreased circulating plasma levels of known pro-inflammatory markers IL-6, MCP-1, IL-1β, IFN-γ and TNF-α. These findings indicate that TPM treatment slows progression of atherosclerotic lesions in ApoE-deficient mice with this effect potentially involving reduced oxidative stress and decreased inflammation.