The causative and infectious agent of the transmissible spongiform encephalopathies, e.g. bovine spongiform encephalopathy in cattle or variant Creutzfeldt–Jakob disease in humans, is a pathogenic form of the scrapie prion protein (PrP Sc) generated by a conformational rearrangement in the normal cellular prion protein (PrP C). Anti-PrP antibodies have been shown to exert a protective effect against infection with PrP Sc. However, the generation of anti-PrP antibodies has proven quite difficult in wild-type animals, PrP being a notoriously poor immunogen. We developed a vaccine against PrP by mixing recombinant murine PrP 23–231 with DnaK, an Hsp70 homolog in Escherichia coli, and cross-linking the two proteins by means of glutaraldehyde. After three injections of the vaccine into BALB/c mice at 6, 8 and 9 weeks of age, a low-titer immune response was detected with ELISA in all animals. The specificity of the antibodies for PrP was confirmed with Western blotting. The straightforward procedure might render active immunization against prion infection feasible.