When considering the clinical applications of autologous cell replacement therapy of human iPSC‐derived cells there is a clear need to better understand what the immune response will be before we embark on extensive clinical trials to treat or model human disease. We performed a detailed assessment comparing human fibroblast cell lines (termed F1) reprogrammed into human iPSC and subsequently differentiated back to fibroblast cells (termed F2) or other human iPSC‐derived cells including neural stem cells made from either retroviral, episomal or synthetic mRNA cell reprogramming methods. Global proteomic analysis reveals the main differences in signal transduction and immune cell protein expression between F1 and F2 cells, implicating wild type toll like receptor protein 3 (TLR3). Furthermore, global methylome analysis identified an isoform of the human TLR3 gene that is not epigenetically reset correctly upon differentiation to F2 cells resulting in a hypomethylated transcription start site in the TLR3 isoform promoter and overexpression in most human iPSC‐derived cells not seen in normal human tissue. The human TLR3 isoform in human iPSC‐NSC functions to suppress NF‐KB p65 signaling pathway in response to virus (Poly IC), suggesting suppressed immunity of iPSC‐derived cells to viral infection. The sustained wild type TLR3 and TLR3 isoform over expression is central to understanding the altered immunogenicity of human iPSC‐derived cells calling for screening of human iPSC‐derived cells for TLR3 expression levels before applications.