Significance Endogenization of retroviruses has occurred multiple times in the course of vertebrate evolution, with the captured retroviral envelope syncytins playing a role in placentation in mammals, including marsupials. Here, we identify an endogenous retroviral envelope protein with unprecedented properties, including a specific cleavage process resulting in the shedding of its extracellular moiety in the human blood circulation. This protein is conserved in all simians—with a homologous protein found in marsupials—with a “stemness” expression in embryonic and reprogrammed stem cells, as well as in the placenta and some human tumors, especially ovarian tumors. This protein could constitute a versatile marker—and possibly an effector—of specific cellular states and being shed, be immunodetected in the blood.