Excessive free radical formation has been implicated as one of the causative factors in neurotoxic damage associated with variety of metals, including methylmercury (MeHg). Although the mechanisms associated with MeHg-dependent neurotoxicity remains are unclear, it is known that MeHg leads to neurotoxicity in cerebellar granule cells (CGCs). In vitro exposure of murine CGC primary cultures to MeHg resulted in time- and concentration-dependent cell death. The present study was designed to assess the effect of fat-soluble antioxidant tocopherols and tocotrienols (unsaturated vitamin E) on MeHg-induced neurotoxicity using cultured CGCs. Significant protection from MeHg-induced neuronal cell death was observed with both tocopherols and tocotrienols. Moreover, we observed that tocotrienols are multi-fold more potent than tocopherols in protecting CGCs against MeHg neurotoxicity. At micromolar concentration, tocotrienols, but not tocopherols, showed complete protection by an antioxidant mechanism. Similarly, tocopherols and tocotrienols showed a protective effect on CGCs migration against MeHg-toxicity. These results suggested that oxidative events may contribute to MeHg toxicity in isolated cerebellar granule neurons, and that tocotrienols are potent supplements for pharmacological protection of the developing brain exposed to MeHg.