A common feature of neurodegenerative disorders is acute or progressive loss of neurons due to apoptosis. The pathological isoform of the prion protein is associated with retinal apoptosis and the cellular isoform (PrPc) has been shown to mediate protection from apoptosis in cell culture and in neonatal retinal explants. Using a model of light-induced photoreceptor apoptosis, we show in vivo that the levels of PrPc expression in the retina inversely correlate with the susceptibility of photoreceptors to light damage. Dissection of apoptotic signalling cascades suggests that PrPc acts neuroprotectively downstream of AP-1 induction. Our results reveal PrP as a neuroprotective/anti-apoptotic factor in vivo and suggest that PrPc may function as a guardian of neuronal integrity.