Prion diseases (e.g., Creutzfeldt-Jakob disease in humans) are always fatal neurodegenerative disorders characterized by conversion of the ubiquitous cellular prion protein (PrP^c) into a pathological conformer. Immunological strategies are considered as promising prophylactic or therapeutic approaches but, unfortunately, vaccination attempts until now have been very disappointing in wild-type animals because of immune tolerance to self PrP^c. Encouraging results have come from recent experiments carried out through genetic immunization (i.e., injection in mice of cDNA coding for murine prion protein [PrP]) or heterologous protein immunization (i.e., injection in mice of PrP from another species), albeit the levels of autoantibodies in wild-type animals remained generally low. Here we investigated whether combining the potential benefits of these two last approaches, namely using genetic immunization with the cDNA coding for a heterologous PrP, could more efficiently break immune tolerance. Wild-type mice were thus vaccinated with cDNA coding for human PrP^c, fused or unfused to a stimulatory T-cell epitope, using or not using electrotransfer of DNA. After three DNA injections, mice receiving electrotransferred DNA developed a strong immune response, oriented toward the humoral Th2 type, characterized not only by high IgG1 and IgG2a antibody titers against the heterologous human PrP^c, but also, as expected, by significant amounts of autoantibodies recognizing the native conformation of murine PrP^c expressed on cell membranes as revealed by flow cytometry and immunofluorescence. These results hence open the way for investigation of the possible protective effects of anti-PrP^c autoantibodies in infected mouse models. More generally, our results suggest that this original immunization strategy could be of value for circumventing tolerance to poorly immunogenic proteins.