Prions are proteinaceous infectious agents postulated to be the causative agents of a group of fatal neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). A known iatrogenic transmission route of TSEs to humans occurs via prion-contaminated surgical instruments or biological materials. Prions, unlike most common pathogens, exhibit an extraordinary resistance to conventional decontamination procedures. We have recently demonstrated that the application of TiO₂-based heterogeneous photocatalytic oxidation is able to significantly reduce prion infectivity. The present study investigates the potential of a homogeneous photocatalytic method, based on the photo-Fenton reagent, to degrade prion proteins. We show that the photo-Fenton reagent efficiently degrades not only recombinant prion proteins, but also the total protein amount from brain preparations of naturally or experimentally infected species and PrP^Sc (PrP scrapie) contained in sheep scrapie brain homogenates.