Silica nanoparticles (NPs) have remarkable applications. However, accumulating evidence suggests NPs can cause cellular toxicity by inducing ROS production and increasing intracellular Ca(2+) ([Ca(2+)]i), but the underlying molecular mechanism is largely unknown. Transient receptor potential melastatin 2 (TRPM2) channel is known to be a cellular redox potential sensor that provides an important pathway for increasing the [Ca(2+)]i under oxidative stress. In this study, we examined the role of TRPM2 channel in silica NPs-induced oxidative stress and cell death. By quantitation of cell viability, ROS production, [Ca(2+)]i, and protein identification, we showed that TRPM2 channel is required for ROS production and Ca(2+) increase induced by silica NPs through regulating NADPH oxidase activity in HEK293 cells. Strikingly, HEK293 cells expressing low levels of TRPM2 were more susceptible to silica NPs than those expressing high levels of TRPM2. Macrophages from young mice showed significantly lower TRPM2 expression than those from senescent mice and had significantly lower viability after silica NPs exposure than those from senescent ones. Taken together, these findings demonstrate for the first time that TRPM2 channel acts as an oxidative stress sensor that plays a dual role in silica NPs-induced cytotoxicity by differentially regulating the NADPH oxidase activity and ROS generation.