Estrogen-related receptor alpha (ERR ) is primarily thought to regulate energy homeostasis through interacting with peroxisome proliferator-activated receptor coactivator-1 and -1 (PGC-1 and -1 ). They coordinately control the transcription of genes in the oxidative phosphorylation pathway. In addition to its role in energy metabolism, ERR has also been implicated as a prognostic marker for breast, ovarian, colon and prostate cancers. In this study, we found that an ERR inverse agonist XCT-790 induced cell death in HepG2 hepatocarcinoma and its multi-drug resistance (MDR) sub-line R-HepG2. Using a dye Mitotracker Green which stains mitochondrion independent of mitochondrial membrane potential ( m), we found that XCT-790 dose-dependently decreased mitochondrial mass. Intriguingly, XCT-790 eactive oxygen species (ROS) increased m upon short term treatment but decreased m upon longer term treatment. The changes of m in turn promoted the production of reactive oxygen species (ROS) and led to ROS-mediated caspases 3/7, 8, 9 activation and cell death. Importantly, we established that an anti-oxidative compound Mn(III) Tetra(4-benzoic acid) porphyrin chloride (MnTBAP) blocked the caspases activities and cell death increased by XCT-790 treatment. Finally, we found that XCT-790 synergized with paclitaxel to induce cell death in multi-drug resistance sub-line R-HepG2. Our results provide a conceptual framework for further developing chemotherapeutics based on suppressing ERR activity.