The effect of water extracts of Djulis (Chenopodiun formosaneum) (WECF) and its bioactive compounds on the oxidative stress of tert-butyl hydroperoxide (t-BHP)-induced HepG2 cells is investigated. WECF (at 10-250 mu g/ml) demonstrates a cytoprotection in 0.2 mM t-BHP-induced HepG2 cells. The oxidative damage was accompanied by depletion of glutathione (GSH), thiobarbituric acid reactive substances (TBARS) formation and reactive oxygen species (ROS) generation which was significantly reduced by WECF. There was a down-regulated degradation of I kappa B-alpha and anti-apoptosis in t-BHP-induced cells by WECF. The increase in the Bcl-2/Bax ratio and the mitochondrial membrane potential and a decrease in caspase-3 activity and the down-modulated degradation of poly ADP-ribose polymerase (PARP) by WECF in t-BHP-induced cells parallels the effect on cell viability. The anti-apoptosis in t-BHP-induced cells by WECF was verified by observation using DAPI staining assay. According to HPLC-DAD and HPLC-MS/MS analysis, betanin, rutin, kaempferol and another twenty compounds were present in WECF, which may partially be responsible for its protective effect against oxidative damage. Collectively, WECF consisting of bioactive compounds can prevent oxidative stress by enhancing the antioxidant indices and reducing apoptosis of cells.