Normal prion protein (PrPC) is a copper binding protein and may play a role in cellular resistance to oxidative stress. Recently, copper-bound recombinant PrPC has been shown to exhibit superoxide dismutase (SOD)-like activity. However, as PrPC affinity for copper is low in comparison to other cupro-proteins, the question remains as to whether PrPC could contribute SOD activity in vivo. To unravel this enigma, we compared the SOD activity in lysates extracted from different regions of the brain from wild-type mice before and after the depletion of PrPC. We found that removal of PrPC from the brain lysates reduced the levels of total SOD activity. The level of contribution to the total SOD activity was correlated to the level of PrP expressed and to the predominant form of PrP present in the specific brain region. Collectively, these results provide strong evidence that PrPC differentially contributes to the total SOD activity in vivo.