Humanized NOD/Shi-scid/interleukin-2Rgamma(null) (NOG) mice with full T cell development had significantly longer life span after Epstein-Barr virus (EBV) infection, compared with those with minimal T cell development. Removing CD3(+) or CD8(+) T cells from EBV-infected humanized mice by administration of anti-CD3 or anti-CD8 antibodies reduced their life span. CD8(+) T cells obtained from EBV-infected mice suppressed the outgrowth of autologous B cells isolated from uninfected mice and inoculated with EBV in vitro. These results indicate that humanized NOG mice are capable of T cell-mediated control of EBV infection and imply their usefulness as a tool to evaluate immunotherapeutic and prophylactic strategies for EBV infection.