Abstract Although CD8 T cells are considered important in controlling HHV-8 (aka KSHV) infection, the etiologic agent of Kaposi’s sarcoma (KS), there is little evidence to support this. Moreover, these T cell responses are relatively non-robust, suggesting that they are under tight regulatory control. We conducted a comprehensive, non-concurrent prospective study of the effect of Treg on CD8 T cell reactivity to HHV-8 lytic and latency proteins in HHV-8 monoinfected, healthy subjects compared to untreated, HHV-8/HIV-1 coinfected subjects who did and did not develop KS in the Multicenter AIDS Cohort Study. Direct staining of PBMC with MHCI multimers showed a relatively high frequency of HHV-8 antigen-specific CD8 T cells compared to low functional T cell activity (IFN-γ ELISPOT) in response to HHV-8 lytic and latency proteins and HIV-1 Gag beginning many years prior to development of KS. Removal of Treg enhanced HHV-8 specific, IFN-γ production by CD8 T cells, with or without HIV-1 coinfection and KS. These data show that beginning very early in HHV-8/HIV-1 coinfection, low antiviral T cell responses are related to eventual development of KS. Moreover, Treg suppress CD8 T cell responses to HHV-8 antigens, effectively masking more robust, underlying anti-HHV-8 T cell responses. The involvement of CD8 T cells and Treg in control of HHV-8 infection has important implications for understanding HHV-8 immunopathogenesis and development of vaccines to prevent KS.