Human embryonic stem cells (hESCs) hold great promise for regenerative medicine as an unlimited source of cells for replacement of the tissues destroyed by injuries or diseases. One of the major impediments of fully realizing its poetical is the immune rejection from allogenic recipients. To overcome the histocompatibility, we established hESCs that lack the expression of Major Histocompatibility Complex (MHC) class I or II, which are the primary mediators for allograft rejection.  Briefly, CRIPR-Cas9n was used to delete exon 1 of beta-2 micro globulin (B2M), leading to a complete deficiency of MHC I on the cell surface of hESCs. In the same manner, exon 2 and 3 of Class II transactivator (CIITA) were deleted, aiming to abrogate any potential of inducible MHC II expression in hESCs. Despite of this genetic manipulation, MHC I-deficient hESCs maintained its self renewal capacity, expressed pluripotent genes and were pluripotent as indicated by their ability to form teratoma in NSG mice. Moreover, we demonstrated that the teratoma derived from MHC I - deficient hESCs were immune protected in Hu-mouse reconstituted with allogenic human immune system, while the teratoma from the parental hESCs showed apparent tissue necrosis and a mount of T cell infiltration, an indication of immune rejection. All these findings indicate that our MHC I-deficient hESCs are hypoimmunogenic, and might be employed as an appealing source of cells for tissue replacement in cell-based therapy without requiring the long-term systemic immune suppression.