Primary immunodeficiencies in the co-stimulatory molecule CD27 and its ligand CD70 predispose for pathologies of uncontrolled Epstein Barr virus (EBV) infection in nearly all affected patients. We demonstrate that both depletion of CD27 positive cells and antibody blocking of CD27 interaction with CD70 causes uncontrolled EBV infection in mice with reconstituted human immune system components. While overall CD8+ T cell expansion and composition is unaltered after antibody blocking of CD27, only some EBV specific CD8+ T cell responses, exemplified by early lytic EBV antigen BMLF1 specific CD8+ T cells are inhibited in their proliferation and killing of EBV transformed B cells. This suggests that CD27 is not required for all CD8+ T cell expansions and cytotoxicity, but for a subset of CD8+ T cell responses that protect us from EBV infection.