The present study demonstrates that the quality of the virus‐specific CD8⁺ T cell responses, as detected by both enzyme‐linked immunospot assay and specific MHC‐peptide tetramers, changed in relation to the different disease activity in chronically hepatitis C virus‐infected patients. Indeed, both the serum alanine transaminase and the hepatic flogosis levels were related directly to the frequencies of peripheral memory effector CD8⁺ T cells producing IFN‐γ (Tc1), but inversely to the frequencies of those producing both IL‐4 and IL‐10 (Tc2). Longitudinal studies highlighted that Tc1 or Tc2 responses fluctuate in relation to the different phases of the disease in the same individual. Furthermore, the Tc1 or Tc2 phenotype correlates with tetramer‐positive cells expressing either CXCR3 or CCR3, promoting differential tissue localization of these cells and the maintenance of T cell homeostasis. Finally, studies at the level of liver‐infiltrating lymphocytes indicated that they produced both IFN‐γ and IL‐4 with an evident bias towards the Tc1‐like phenotype. Our studies suggest that the progressive fluctuation of Tc1 and Tc2 responses may play a fundamental role in maintaining a long‐lasting low‐level liver inflammation, and may constitute the basis for new therapeutic strategies of immune regulation.