Over 170 million people worldwide are infected with hepatitis C virus (HCV) The immune system is effective at clearing the virus in a small proportion o f infected individuals while most people become persistently infected with the virus and develop chronic liver disease. Natural killer (NK) cells are thought to mediate immunity against viruses. They can lyse virus infected cells and release anti-viral cytokines. The roles of NK cells and natural killer receptor positive (NKR+) T cells in immunity agamst HCV is largely unknown. The aim o f the present study was to investigate the hypothesis that NK cells and NKR+ T cells numbers and/or functions are depleted in patients with chronic HCV infection. Flow cytometry was used to evaluate the numbers and phenotypes o f NK cell and NKR+ T cells in peripheral blood o f 33 patients with chrome HCV infection, 22 patients who spontaneously resolved HCV infection and 26 healthy controls. Natural cytotoxicity and interleukin-2-activated killing o f K562 and Daudi cells by peripheral blood mononuclear cells (PBMCs) were assessed using 5'chromium release assays. NK cells and NKR+ T cells were depleted in patients with chronic HCV compared to the healthy controls (3.4% vs 13.7% for NK cells; p<0.001 and 1.3% vs 3.7% for CD56+ T cells; p=0.0001). NK cells and CD56+ T cells were also depleted in HCV resolvers compared to controls. The frequencies o f expression o f CD16, CD56, CD161, KIR2DL1 and KIR3DL1/S1 by T and non-T cells were also altered in chronic HCV patients compared to controls. Natural cytotoxicity by PBMCs against K562 cells was impaired in patients with chronic HCV infection compared with controls (mean specific lysis at effector/target ratios o f 50:1 were 1.8% vs 10.2%; p<0.001) and HCV resolvers (7.4%, p=0.0012). IL-2 induced cytotoxicity against K562 and Daudi targets was also impaired in patients with chronic HCV disease compared to HCV resolvers and controls (2.4% vs 7.6% and 12.6% respectively, p<0.001 for K562 and 0% vs 2.5% and 8.1%; p<0.001 for Daudi). Spearman analysis indicated that the impaired cytotoxic activity and LAK activity in the patients is not solely due to decreased NK or NKR+ T cell numbers. This study suggests that altered NK levels and activities are associated with HCV infection and may be responsible, at least in part, for the chronicity of the infection