The importance of human herpesvirus 6 (HHV-6) species as human pathogens is increasingly appreciated. However, we do not understand how infection is controlled in healthy virus carriers, and why control fails in patients with disease. Other persistent viruses are under continuous surveillance by antigen-specific T cells, and specific T-cell repertoires have been well characterized for some of them. In contrast, knowledge on HHV-6-specific T-cell responses is limited, and missing for CD8+ T cells. Here we identify CD8+ T-cell responses to HHV-6B, the most widespread HHV-6 species, in healthy virus carriers. HHV-6B-specific CD8+ T-cell lines and clones recognized HLA-A2-restricted peptides from the viral structural proteins U54 and U11, and displayed various antigen-specific antiviral effector functions. These CD8+ T cells specifically recognized HHV-6B-infected primary CD4+ T cells in an HLA-restricted manner, produced antiviral cytokines, and killed infected cells, whereas HHV-6A-infected cells were not recognized. Thus, HHV-6B-specific CD8+ T cells are likely to contribute to control of infection, overcoming the immunomodulatory effects exerted by the virus. Potentially, HHV-6-associated disease could be addressed by active or passive immunotherapy that reconstitutes virus-specific CD8+ T-cell responses.