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.