BACKGROUND Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG). AIM To investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B. METHODS The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus (HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects. RESULTS The ability of NK cells to produce IFN-gamma was markedly attenuated in HBV-infected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-alpha production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEG phases, as evidenced by the upregulation of NKp44 in CD56(bright) NK cells and CD69 in CD56(dim) NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-gamma and TNF-alpha expression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases. CONCLUSION Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.