CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope–specific and hepatitis C virus (HCV)–specific CD8+ T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA+ cell subsets expressing a dysfunctional T-helper 1–like signature program in chronic HCV infection. However, apoptotic epitope–specific CD8+ T cells produced tumor necrosis factor α and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8+ T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope–specific CD8+ T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8+ T cells, apoptotic epitope–specific CD8+ T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor α, and exhibit greater resistance to inhibitory signals during chronic HCV infection.