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Sirtuin 2 (SIRT2) is a member of the sirtuin family. Previous studies have suggested that SIRT2 mediates the cell death in models of Parkinson’s disease and Huntington’s disease. However, the role of SIRT2 in oxidative stress-induced cell death has remained unclear. In this study, we investigated the roles of SIRT2 in oxidative stress-induced cell death using differentiated PC12 cells as a cell model. We found that H2O2 induced a significant increase in the SIRT2 level in the cells. Both SIRT2 silencing and the SIRT2 inhibitor AGK2 significantly decreased H2O2-induced apoptosis, partially by inhibiting caspase-3 activation. We further found that silencing of SIRT2 led to decreased reactive oxygen species levels in the H2O2-treated cells. Collectively, our observations have suggested that SIRT2 plays a significant role in oxidative stress-induced cell death.