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Objective: To investigate the cytoprotective effects of Saeng-kankunbi-tang(生肝健脾汤, SKT), a herbal prescription consisting of Artemisia capillaris and Alisma canaliculatum, and its underlying mechanism involved. Methods: In mice, blood biochemistry and histopathology were assessed in carbon tetrachloride(CCl4)-induced oxidative hepatic injury in vivo. The animal groups included vehicle-treated control, CCl4, SKT 500 mg/(kg·day) CCl4+SKT 200 or 500 mg/(kg·day). In Hep G2 cell, tert-butyl hydroperoxide(t BHP) induced severe oxidative stress and mitochondrial dysfunction in vitro. The cyto-protective effects of SKT were determined by 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide(MTT) assay, fluorescence activated cell sorting analysis and western blotting. Results: The administration of SKT prevented liver damage induced by CCl4 in mice, by inhibition of hepatocyte degeneration and inflammatory cell infiltration as well as plasma parameters such as alanine aminotransferase(P<0.01). Moreover, treatment with t BHP induced hepatocyte death and cellular reactive oxygen species production in hepatocyte cell line. However, SKT pretreatment(30–300 μg/m L) reduced this cell death and oxidative stress(P<0.01). More importantly, SKT inhibited the ability of t BHP to induce changes in mitochondrial membrane transition in cell stained with rhodamine 123(P<0.01). Furthermore, treatment with SKT induced extracellular signal-regulated kinases-mediated nuclear factor erythroid-2-related factor 2(Nrf2) activation as well as the expressions of heme oxygenase 1 and glutamate-cystein ligase catalytic, Nrf2 target genes. Conclusion: SKT has the ability to protect hepatocyte against oxidative stress and mitochondrial damage mediated by Nrf2 activation.