Objective: To define the cross-reactivity potential and the consequent autoimmunity intrinsic to viral versus human peptide sharing. Methods: Using human papillomavirus (HPV) infection/active immunization as a research model, the experimentally validated HPV L1 epitopes catalogued at the Immune Epitope DataBase were analyzed for peptide sharing with the human proteome. Results: The final data show that the totality of the immunoreactive HPV L1 epi-topes is mostly composed by peptides present in human proteins. Conclusions: Immunologically, the high extent of peptide sharing between the HPV L1 epitopes and human proteins invites to revise the concept of the negative selection of self-reactive lymphocytes. Pathologically, the data highlight a cross-reactive potential for a spectrum of autoimmune diseases that includes ovarian failure, systemic lupus erythematosus (SLE), breast cancer and sudden death, among others. Therapeutically, analyzing already validated immunoreactive epitopes filters out the peptide sharing possibly exempt of self-reactivity, defines the effective potential for pathologic autoimmunity, and allows singling out peptide epitopes for safe immunotherapeutic protocols.