Abstract Aging is accompanied by a complex dynamics of CD8þ T cell subsets whose origin is unclear. To evaluate the impact of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) chronic infections on CD8þ T cells in far advanced age, we studied CD8þ T cells frequencies and phenotype in nonagenarians and centenarians by HLA-A*0201- and HLA-B*0702-tetramers incorporating epitopes specific of both viruses along with viral replication. The results demonstrate that EBV and CMV infections induce quantitatively and qualitatively different CD8þ Tcell responses in advanced aging. The frequency and absolute number of CD8þ T cells specific for one lytic and two latent EBV-epitopes, were relatively low and mostly included within CD8þ CD28þ cells. By contrast, CMV infection was characterized by highly variable numbers of CD8þ T cells specific for two differently restricted CMV-epitopes that, in some subjects, were strikingly expanded. Moreover, the great majority of anti-CMV CD8þ T cells did not bear CD28 antigen. Notwithstanding the expansion of CMV-specific CD8þ lymphocytes, CMV-DNA detection in blood samples was invariably negative. Altogether, we suggest that CMV, but not EBV, can sustain chronic activation of the HLA-class I restricted effector arm in elderly that might have detrimental effects on age-associated diseases.