T cells specific for a single viral epitope, but using different T cell receptors, should have flexibility in their epitope recognition to protect the infected host against the emergence of viral escape mutants. Therefore, polyclonality of the hepatitis B virus (HBV)‐specific cytotoxic T lymphocyte response has been hypothesized to be a major determinant in the control of infection. We analyzed the Vβ chain composition of the core 18‐27‐specific CD8 cells in acute and persistently HBV‐infected patients using HLA‐A2 tetrameric complexes and a panel of Vβ antibodies. Different T cell receptors were utilized by core 18‐27‐specific CD8 cells both in patients with acute and chronic infection. The functional ability of these epitope‐specific T cells to respond to potential viral mutations was then tested. The polyclonal HBV‐specific CD8 response present in patients with acute hepatitis displayed a limited efficiency to recognize mutations introduced within the epitope. The ability of core 18‐27‐specific CD8 to tolerate epitope mutations was found only during persistent HBV infection. The data suggest that although a clonally heterogeneous CD8 response can be largely inhibited by the occurrence of single epitope mutations in primary HBV infection, preferential selection of T cells able to counteract the emergence of viral mutations can occur during persistent infection.