The N-terminal region of the prion protein PrPC contains a series of octapeptide repeats. This region has been implicated in the binding of divalent metal ions, particularly copper. PrPC has been suggested to be involved in copper transport and metabolism and in cell defense mechanisms against oxidative insult, possibly through the regulation of the intracellular CuZn superoxide dismutase activity (CuZn-SOD) or a SOD-like activity of PrPC itself. However, up to now the link between PrPC expression and copper metabolism or SOD activity has still to be formally established; particularly because conflicting results have been obtained in vivo. In this study, we report a link between PrPC, copper binding, and resistance to oxidative stress. Radioactive copper (64Cu) was used at a physiological concentration to demonstrate that binding of copper to the outer plasma cell membrane is related to the level of PrPC expression in a cell line expressing a doxycycline-inducible murine PrPC gene. Cellular PIPLC pretreatment indicated that PrPC was not involved in copper delivery at physiological concentrations. We also demonstrated that murine PrPC expression increases several antioxidant enzyme activities and glutathione levels. Prion protein may be a stress sensor sensitive to copper and able to initiate, following copper binding, a signal transduction process acting on the antioxidant systems to improve cell defenses.