A pathological hallmark of Alzheimer’s disease is an accumulation of insoluble plaque containing the amyloid-β peptide of 40–42 amino acid residues. Prefibrillar, soluble oligomers of amyloid-β have been recognized to be early and key intermediates in Alzheimer’s-disease-related synaptic dysfunction^,,,,,,,. At nanomolar concentrations, soluble amyloid-β oligomers block hippocampal long-term potentiation, cause dendritic spine retraction from pyramidal cells^, and impair rodent spatial memory. Soluble amyloid-β oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer’s disease brain^,,,. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-β oligomers on neurons—one that is central to the pathophysiological process in Alzheimer’s disease. Here we identify the cellular prion protein (PrP^C) as an amyloid-β-oligomer receptor by expression cloning. Amyloid-β oligomers bind with nanomolar affinity to PrP^C, but the interaction does not require the infectious PrP^Sc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrP^C and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrP^C is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrP^C-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.