The inability of patients with chronic HBV infection to clear HBV is associated with defective HBV-specific CD8 ⁺ T cells. Hence, the majority of immunotherapy developments focus on HBV-specific T cell function restoration. However, knowledge of whether distinct HBV-specific T cells can equally target all the HBV-infected hepatocytes of a chronically infected liver is lacking. In this work, analysis of CHB patient liver parenchyma and in vitro HBV infection models shows a nonuniform distribution of HBV CD8 ⁺ T cell epitopes that is influenced by the presence of IFN-γ and availability of newly translated viral antigens. These results suggest that CD8 ⁺ T cells recognizing different HBV epitopes can be necessary for efficient immune therapeutic control of chronic HBV infection.