Taking advantage of the inbred mouse strain that has identical genetic background, we produce integration-free mouse iPSCs that can be transplanted back into genetically identical mice. In contrast to the popular belief, our findings indicate that cells differentiated from mouse iPSCs are immunogenic in the genetically identical mice. We further show that this immunogenicity is due to the abnormal expression of immunogenic proteins during the differentiation of iPSCs, possibly as a result of the abnormal DNA methylation of the genome of iPSCs. In summary, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients