Acute neurotoxic effects of high dose methylmercury (MeHg) in humans have been well documented in the scientific literature. However, low dose effects are less well described. This study was designed to evaluate the effects of low dose MeHg (<100 nM) on human brain cells in a tissue culture model. Neuroblastoma cells (SH-Sy5y) were used in the cell culture model to study low dose effects of MeHg on cell growth, cell survival, oxidative stress and the phosphorylation of tau protein, as a measure of potential markers of cellular events associated with tauopathies. When cells were incubated in culture with MeHg (50 nM and 100 nM), there were significant decreases in cell viability as well as a significant increase in reactive oxygen species. In addition, the level of phosphorylated tau was significantly increased following treatment at both 50 nM and 100 nM MeHg, as compared to controls. Pretreatment of neuroblastoma cells with the antioxidant, N-acetylcysteine, as well as a calpain inhibitor, MDL- 28170, significantly attenuated the effects of MeHg (50 nM and 100 nM) on cell viability as well as on tau phosphorylation. Furthermore, MeHg has also been reported to alter glutamate homeostasis in the neuronal environment, resulting in excitotoxicity. Exposure of cells to a combination of MeHg (50 nM) and glutamate (1 mM) resulted in a greater decrease in cell viability as well as a greater induction in tau phosphorylation, as compared to exposures with MeHg and glutamate alone. MK-801 (4 μM), an NMDA receptor antagonist, and the intracellular calcium chelator, BAPTA-AM, both significantly inhibited tau hyperphosphorylation and protected cells from the effects of combination exposures to glutamate and MeHg. This study suggests that MeHg may increase the cellular response to glutamate thereby enhancing its excitoxicity. The overall conclusion of this work is that, low dose MeHg toxicity in neuroblastoma cells may be related to its induction of tau phosphorylation through an induction of oxidative stress, alteration in intracellular calcium levels as well as activation of μ-calpain and that blockade of this pathway may produce protective effects against MeHg induced neurological effects.