Aims. The cellular prion protein, PrPC, whose aberrant isoforms are related to prion diseases of humans and animals, has a still obscure physiologic function. Having observed an increased expression of PrPC in two in vivo paradigms of heart remodelling, we focused on isolated mouse hearts to ascertain the capacity of PrPC to antagonize oxidative damage induced by ischemic and non-ischemic protocols. Methods and results. Hearts isolated from mice expressing PrPC in variable amounts were subjected to different and complementary oxidative perfusion protocols. Accumulation of reactive oxygen species, oxidation of myofibrillar proteins and cell death were evaluated. We found that overexpressed PrPC reduced oxidative stress and cell death caused by post-ischemic reperfusion. Conversely, deletion of PrPC increased oxidative stress during both ischemic preconditioning and perfusion (15 min) with H2O2. Supporting its relation with intracellular systems involved in oxidative stress, PrPC was found to influence the activity of catalase and, for the first time, the expression of p66Shc, a protein implicated in oxidative stress-mediated cell death. Conclusions. Our data demonstrate that PrPC contributes to the cardiac mechanisms antagonizing oxidative insults.