The mechanisms leading to neurodegeneration are complex and multifactorial. Oxidative stress has been identified as an important constituent in this process and the use of transgenic and knockout mice has allowed the role of key components of the antioxidant pathway to be evaluated. In this study, we have used mice lacking the glutathione peroxidase-1 gene in order to determine the consequences of a reduced capacity to neutralize hydrogen peroxide toward the pathological outcomes following cold-induced brain injury. Analysis of brain cryosections using TUNEL staining revealed a significant increase in brain cell death in knockout mice compared to that seen in wild-type mice. Interestingly, cell death appeared to be uncoupled to a neuro-inflammatory response which was observed in both knockout and wild-type mice but which proceeded in an accelerated manner in glutathione peroxidase-1 knockout mice at 24 h, rapidly diminishing by 96 h postinjury. Our data suggest an important role for glutathione peroxidase-1 in modulating molecular pathways involved in both the level of cell death and inflammatory cascades in brain through its antioxidant capacity in regulating levels of oxygen species such as hydrogen peroxide.