In Alzheimer disease (AD), amyloid-β (Aβ) oligomer is suggested to play a critical role in imitating neurodegeneration, although its pathogenic mechanism remains to be determined. Recently, the cellular prion protein (PrP C) has been reported to be an essential co-factor in mediating the neurotoxic effect of Aβ oligomer. However, these previous studies focused on the synaptic plasticity in either the presence or the absence of PrP C and no study to date has reported whether PrP C is required for the neuronal cell death, the most critical element of neurodegeneration in AD. Here, we show that Prnp -1- mice are resistant to the neurotoxic effect of Aβ oligomer in vivo and in vitro. Furthermore, application of an anti-PrP C antibody or PrP C peptide prevents Aβ oligomer-induced neurotoxicity. These findings are the first to demonstrate that PrP C is required for Aβ oligomer-induced neuronal cell death, the pathology essential to cognitive loss.