Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are rare and fatal neurodegenerative conditions that affect both humans and animals. Although there is increased evidence that oxidative stress plays an important role in the pathogenesis of these diseases, the direct relationship between an accumulation of abnormal prion protein (PrP(Sc)) and the occurrence of oxidative stress has not been studied. In the present study, we have investigated the cellular localization of proteins modified by lipid peroxidation end products and its correlation with PrP(Sc) accumulation in the brain of mice infected with the ME7 prion strain. Intense immunostaining of malondialdehyde (MDA)- and hydroxynonenal (HNE)-modified proteins were observed in the hippocampus of prion-infected mice. In serial section study, we found that these immunoreactivities were co-localized with glial fibrillary acidic protein (GFAP)-positive astrocytes as well as with PrP(Sc). These results clearly indicate that the heightened oxidative stress in the form of lipid peroxidation is closely associated with PrP(Sc) accumulation in astrocytes of prion-infected mice.