Prion diseases are caused by conformational alterations in the prion protein (PrP). The immune system has been assumed to be non‐responsive to the self‐prion protein, therefore, PrP autoimmunity has not been investigated. Here, we immunized various strains of mice with PrP peptides, some selected to fit the MHC class II‐peptide binding motif. We found that specific PrP peptides elicited strong immune responses in NOD, C57BL/6 and A/J mice. To test the functional effect of this immunization, we examined the expression of proteinase‐K‐resistant PrP by a scrapie‐infected tumor transplanted to immunized syngeneic A/J mice. PrP peptide vaccination did not affect the growth of the infected tumor transplant, but significantly reduced the level of protease‐resistant PrP. Our results demonstrate that self‐PrP peptides are immunogenic in mice and suggest that this immune response might affect PrP‐scrapie levels in certain conditions.