SIRT3 is a NAD+-dependent protein deacetylase localized in mitochondria. Although several previous studies reported cytoplasmic and/or nuclear localization of SIRT3, extra-mitochondrial SIRT3 was obscure. We found that mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs were expressed in the mouse brain and diffuse SIRT3 immunostaining in cytoplasm was detected in cultured neural cells and neural precursor cells where SIRT3 knockdown disturbed neural precursor cell differentiation. However, overexpression of SIRT3 in COS7 cells showed that expression levels of SIRT3ct was much lower than that of SIRT3mt. SIRT3ct but not SIRT3mt was promptly degraded by the ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by the ubiquitination of NH2-terminal methionine and partly by that of lysine residues. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. The overexpression of SIRT3ct decreased cell death by H2O2 at similar levels achieved by that of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death by amyloid-b (Ab) and the overexpression of SIRT3ct opposed the toxic function of Ab in PC12 cells. These results indicated that SIRT3ct participated in cell survival under various stress conditions.