Methylmercury is an environmental pollutant that causes severe central nervous system damage. However, the mechanism involved in its toxicity remains unclear. In this study, expression of thioredoxin-interacting protein (TXNIP), which is involved in the regulation of intracellular redox status, was rapidly induced in mouse neuronal C17.2 cells in response to methylmercury exposure. In addition, C17.2 cells transfected with small interfering RNA against TXNIP mRNA showed greater resistance to methylmercury than control cells. These findings suggest that TXNIP is a novel factor involved in enhancing methylmercury toxicity and that methylmercury may cause cell death by inducing TXNIP expression.