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Background & Aims: The phenotypic and functional characteristics of natural killer (NK) cells in chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are incompletely defined and largely controversial. Methods: We studied NK cell receptor expression, cytotoxic activity, and cytokine production in peripheral blood mononuclear cells from 35 patients with chronic hepatitis C, 22 with chronic hepatitis B, and 30 healthy controls. Results: Patients with chronic HBV infection had an increased proportion of NKG2C+ NK cells with normal inhibitory receptor expression and a lower proportion of activated NK cells compared with HCV+ patients, which was associated with normal or reduced cytolytic activity and markedly dysfunctional tumor necrosis factor-α and interferon-γ production. Patients with chronic HCV infection showed a predominantly activating phenotype, featuring a decreased percentage of cells expressing the inhibitory receptor KIR3DL1 and a concomitant increase in the proportion of NKG2D+ NK cells. Expression of the CD69 early activation antigen on NK cells positively correlated with serum alanine aminotransferase and HCV RNA values, suggesting participation of virus-induced effector NK cells in liver necroinflammation. Phenotypic changes in HCV+ patients were associated with enhanced cytokine-induced cytolytic activity and increased usage of natural cytotoxicity and NKG2D receptor pathways, accompanied by defective cytokine production, although to a lesser extent than patients with chronic HBV infection. Conclusions: These findings provide evidence for a functional dichotomy in patients with chronic HBV and HCV infections, featuring conserved or enhanced cytolytic activity and dysfunctional cytokine production, which may contribute to virus persistence. [Copyright &y& Elsevier]