To enable cell therapy on a broader scale, the development of universal donor stem cell products that can be administered to multiple patients in need, has been proposed, yet a strategy controlling both adaptive and innate immune rejection has not been reported. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells (hPSCs). Furthermore, to prevent innate immune rejection and further suppress adaptive immune responses, we expressed the immunomodulatory factors PD-L1, HLA-G, and the macrophage ‘don’t-eat me’ signal CD47, from the AAVS1 safe harbor locus. Importantly, gene-edited stem cell lines could be differentiated into disease-relevant cell types, such as endothelial cells and vascular smooth muscle cells, and only showed minimal off-target effects. Utilizing in vitro and in vivo immunoassays, we found that T cell responses were blunted. Moreover, NK cell killing and macrophage engulfment of our engineered cells was minimal. Our strategy demonstrates the power of cell engineering and informs future studies aiming to generate “off-the-shelf” universal cell products that may therefore enable cell therapy on a broader scale.