Prion diseases are fatal neurodegenerative disorders resulting from conformational changes in the prion protein from its normal cellular isoform, PrP C , to the infectious scrapie isoform, PrP S c . In spite of many studies, the physiological function of PrP C remains unknown. Recent work shows that PrP C binds Cu 2 + , internalizing it into the cytoplasm. Since many antioxidant enzymes depend on Cu 2 + (e.g., Cu/ZnSOD), their function could be affected in prion diseases. Here we investigate a possible relationship between PrP C and the cellular antioxidant systems in different structures isolated from PrP C knockout and wild-type mice by determining oxidative damage in protein and lipids and activity of antioxidant enzymes (CAT, SOD) and stress-adaptive enzymes (ODC). Our results show that, in the absence of PrP C , there is an increased oxidation of lipid and protein in all structures investigated. Decreased SOD activity and changes in CAT/ODC activities were also observed. Taking into account these results, we suggest that the physiological function of PrP C is related to cellular antioxidant defenses. Therefore, during development of prion diseases, the whole organism becomes more sensitive to ROS injury, leading to a progressive oxidative disruption of tissues and vital organs, especially the central nervous system.