Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) is associated with poor graft- and patient-survival. Treatment with HBV-specific immunoglobulins (HBIG) in combination with nucleos(t)ide analogs is effective in preventing HBV reinfection of the graft and improving OLT outcome. However, the role of HBV-specific cellular immunity in viral containment in immune suppressed patients in general and in OLT recipients in particular is unclear. To test whether or not OLT recipients maintain robust HBV-specific cellular immunity, the cellular immune response against HBV was assessed in 15 OLT recipients and 27 individuals with chronic and 24 subjects with self-limited HBV infection, respectively; using an overlapping peptide set spanning the viral nucleocapsid- and envelope-protein sequences. The data demonstrate that OLT recipients mounted fewer but stronger clusters of differentiation (CD)8 T cell responses than subjects with self-limited HBV infection and showed a preferential targeting of the nucleocapsid antigen. This focused response pattern was similar to responses seen in chronically infected subjects with undetectable viremia, but significantly different from patients who presented with elevated HBV viremia and who mounted mainly immune responses against the envelope protein. In conclusion, virus-specific CD4 T cell–mediated responses were only detected in subjects with self-limited HBV infection. Thus, the profile of the cellular immunity against HBV was in immune suppressed patients similar to subjects with chronic HBV infection with suppressed HBV-DNA. Liver Transpl 2008. © 2008 AASLD.