Ginseng has long been used in the Asian Countries for more than 2,000 years. Currently, in the âWestern World or Western Medicinesâ, many reports have indicated that they have used herbal medicines, and Ginseng is one of the most popular herbs. Several recent reports have indicated that the antioxidant / anti-oxidative stress activities of ginseng play a role in the benefits of ginseng, however the precise mechanism is lacking. The antioxidant response element (ARE) is a critical regulatory element for the expression of many anti-oxidant enzymes and phase II/III drug metabolizing/transporter genes, mediated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The aim of this study was to examine the potential activation and synergism of Nrf2-ARE-mediated transcriptional activity between three common ginsenosides present in ginseng, ginsenoside Rb1 (Rb1), ginsenoside Rg1 (Rg1) and ginsenoside 20(S)-protopanaxytriol (20S). We tested whether these ginsenosides and their combinations, could induce Nrf2-ARE activities in HepG2-C8 cells with stably transfected ARE luciferase reporter gene. Cell proliferation, antioxidant and ARE activities, western blotting of Nrf2 protein and qPCR of mRNA of Nrf2 were conducted for Rb1, Rg1 and 20S as well as the combinations of 20S with Rb1 or Rg1. To determine the combination effects, the combination index (CI) was calculated. Rb1 and Rg1 are relatively non-toxic to the cells, while 20S at 50 ÎŒM or above significantly inhibited the cell proliferation. Rb1, Rg1 or 20S induced total antioxidant activity and ARE activity in a concentration-dependent manner. Furthermore, combinations of 20S with either Rb1 or Rg1 induced total antioxidant and ARE activity synergistically. Induction of Nrf2 protein and mRNA were also found to be synergistic with the combination treatments. In summary, in this study, we show that ginsenosides Rb1, Rg1 and 20S possess antioxidant activity, transcriptionally activating ARE as well as potential of synergistic activities. The Nrf2-ARE-mediated antioxidant pathway could play a role for the overall anti-oxidative stress activities, which could be important for ginseng's health beneficial effects such as cancer chemopreventive activities.