Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a transcription factor belonging to the superfamily of nuclear receptors. Disruption of the Rora gene in the mouse results in a defect in the development of Purkinje cells leading to a cerebellar atrophy, which suggests a neuroprotective role for RORalpha. To test this hypothesis, the survival rate of lentiviral-mediated human RORalpha1-overexpressing neurones has been evaluated in response to different stressors disturbing the redox homeostasis, such as beta-amyloid peptide, c(2)-ceramide and H(2)O(2). We show that overexpression of human RORalpha1 provides neuroprotection by increasing the expression of the antioxidant proteins glutathione peroxidase 1 and peroxiredoxin 6, leading to a reduction in the accumulation of stress-induced reactive oxygen species. We further demonstrate that the neuroprotective effect of RORalpha is predominantly mediated by glutathione peroxidase 1 and peroxiredoxin 6. These results suggest a new role for RORalpha in the control of the neuronal oxidative stress and thus represents a new transcription factor of interest in the regulation of reactive oxygen species-induced neurodegenerative processes during ageing.