The absence of an immune response to prions—the infectious agents of scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jakob disease—might be related to the fact that these agents do not contain nucleic acids. We aimed to use CpG oligodeoxynucleotides, which have been shown to stimulate innate immunity, as a form of postexposure prophylaxis in mice. We inoculated healthy mice with brain homogenates from mice infected with the RML scrapie prion, and then injected CpG oligodeoxynucleotides. This postexposure prophylaxis with CpG oligodeoxynucleotides resulted in 38% longer survival times than treatment with saline (p<0·0001), or even longer after repeated application. The explanation for this finding remains to be elucidated, but the most likely is stimulation of TLR9-expressing cells of the innate immune system such as macrophages, monocytes, and dendritic cells. CpG oligodeoxynucleotides have not been shown to have adverse effects to human health and could therefore be considered as a therapeutic choice in postexposure prophylaxis.