Dealcoholated red wine has been shown to exert protective effects, reducing the risk of cardiovascular events by improving endothelium-dependent vasodilation and inhibiting platelet aggregation These biological activities have been associated with the polyphenolic components of red wine, suggesting that the pool of phenolic compounds, including flavonoids and anthocyanins, could be responsible for its functional effects. The concept that antioxidant properties of polyphenols could explain the beneficial effects of red wine has been carried forward. Here, we hypothesize a new role of red wine in modulating oxidative stress, leading to the alteration of the antioxidant potential in humans. We previously demonstrated that red wine polyphenols (RWp) protect human erythrocytes from oxidative stress by the activation of an important enzymatic system involved in neutralizing plasma free radicals, namely Plasma Membrane Redox System (PMRS). The present work investigates the underlying mechanism triggered by RWp in the activation of PMRS via the involvement of intracellular GSH. Hence, the increase of GSH intracellular concentration results from the activation of GSH-dependent enzymes, namely glutathione reductase and glucose-6-phosphate dehydrogenase, of about 30% and 50% respectively after 2 min of incubation of human erythrocytes in the presence of RWp (73 ug/ml Gallic Acid Equivalents). Changes in GSH pathway induced by RW were associated with a slight but significant increase (about 15%) of ROS (reactive oxygen species) concentration. We conclude that the pro-oxidant effect of RWp promotes an adaptive stress response in human erythrocytes, which improves their antioxidant defense protecting them from oxidative stress.