Description: The vitamin E family includes both tocopherols and tocotrienols, where α -tocopherol ( α TOC) is the most bioavailable form. Clinical trials testing the therapeutic efficacy of high-dose α TOC against stroke have largely failed or reported negative outcomes when a "more is better" approach to supplementation (〉400 IU/d) was used. This work addresses mechanisms by which supraphysiologic α TOC may contribute to stroke-induced brain injury. Ischemic stroke injury and the neuroinflammatory response were studied in tocopherol transfer protein-deficient mice maintained on a diet containing α TOC vitamin E at the equivalent human dose of 1680 IU/d. Ischemic stroke-induced brain injury was exacerbated in the presence of supraphysiologic brain α TOC levels. At 48 h after stroke, S100B and RAGE expression was increased in stroke-affected cortex of mice with elevated brain α TOC levels. Such increases were concomitant with aggravated microglial activation and neuroinflammatory signaling. A poststroke increase in markers of oxidative injury and neurodegeneration in the presence of elevated brain α TOC establish that at supraphysiologic levels, α TOC potentiates neuroinflammatory responses to acute ischemic stroke. Exacerbation of microglial activation by excessive α TOC likely depends on its unique cell signaling regulatory properties independent of antioxidant function. Against the background of clinical failure for high-dose α TOC, outcomes of this work identify risk for exacerbating stroke-induced brain injury as a result of supplementing diet with excessive levels of α TOC.—Khanna, S., Heigel,M., Weist, J., Gnyawali, S., Teplitsky, S., Roy, S., Sen, C. K., Rink, C. Excessive α -tocopherol exacerbates microglial activation and brain injury caused by acute ischemic stroke.