Neuronal death is a prominent, but poorly understood, pathological hallmark of prion disease. Notably, in the absence of the cellular prion protein (PrP^C), the disease-associated isoform, PrP^Sc, appears not to be intrinsically neurotoxic, suggesting that PrP^C itself may participate directly in the prion neurodegenerative cascade. Here, cross-linking PrP^C in vivo with specific monoclonal antibodies was found to trigger rapid and extensive apoptosis in hippocampal and cerebellar neurons. These findings suggest that PrP^C functions in the control of neuronal survival and provides a model to explore whether cross-linking of PrP^C by oligomeric PrP^Sc can promote neuronal loss during prion infection.