Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA‐E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C+CD56dim NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi‐color flow cytometry revealed that the expanded NKG2C+CD56dim NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN‐γ, and TNF‐α) to stimulation with antibody‐coated as well as HLA‐E expressing target cells but not when stimulated with IL‐12/IL‐18. More importantly, NKG2C+CD56dim NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin‐like receptors (KIRs) specific for self‐HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C‐mediated activation suggesting that such biased expression of self‐specific KIRs may preserve self‐tolerance and limit immune‐pathology during viral infection. Together, these findings shed new light on how the human NK‐cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells.