Abstract: Background: Ginseng has been shown to exert anti-stress effects both in vitro and in vivo. However, the effects of ginseng on stress in brain cells are not well understood. In this study, we investigated how Korean Red inseng (KRG) controls hydrogen peroxide-induced apoptosis via regulation of PI3K/AKT and estrogen receptor β signaling.Methods: Human neuroblastoma SK-N-SH cells were pre-treated with KRG and subsequently exposed to H2O2. The ability of KRG to inhibit oxidative stress-induced apoptosis was assessed in MTT cytotoxicity assays. Apoptotic protein expression was examined by western blot analysis. The roles of ER-β, PI3K, and p-AKT signaling in KRG regulation of apoptosis were studied using small interfering RNAs and/or target antagonists.Results: Pre-treating SK-N-SH cells with KRG decreased expression of the pro-apoptotic proteins p-p53 and caspase-3, but increased expression of the anti-apoptotic protein BCL2. KRG pre-treatment was also associated with increased ERβ, PI3K, and p-AKT expression. Conversely, ER-β inhibition with siRNA or inhibitor treatment increased p-p53 and caspase-3 levels, but decreased BCL2, PI3K, and p-AKT expression. Moreover, inhibition of PI3K/AKT signaling diminished p-p53 and caspase-3 levels, but increased BCL2 expression.Conclusion: Collectively, our data indicate that KRG represses oxidative stress-induced apoptosis by enhancing PI3K/AKT signaling via up-regulation of ER-β expression.