Long-lived “memory-like” NK cells have been identified in individuals infected by human cytomegalovirus (HCMV), but little is known about how the memory-like NK cell pool is formed. Here, we have shown that HCMV-infected individuals have several distinct subsets of memory-like NK cells that are often deficient for multiple transcription factors and signaling proteins, including tyrosine kinase SYK, for which the reduced expression was stable over time and correlated with epigenetic modification of the gene promoter. Deficient expression of these proteins was largely confined to the recently discovered FcRγ-deficient NK cells that display enhanced antibody-dependent functional activity. Importantly, FcRγ-deficient NK cells exhibited robust preferential expansion in response to virus-infected cells (both HCMV and influenza) in an antibody-dependent manner. These findings suggest that the memory-like NK cell pool is shaped and maintained by a mechanism that involves both epigenetic modification of gene expression and antibody-dependent expansion. Display omitted •NK cells with multiple protein deficiencies are present in HCMV-infected individuals•SYK deficiency is associated with hyper-methylation of the gene promoter•Memory-like NK cells have protein deficiencies in combination with FcRγ deficiency•FcRγ-deficient NK cells expand preferentially in an antibody-dependent manner Long-lived “memory-like” NK cells have been identified in HCMV-infected individuals at variable frequencies, but little is known about how this NK cell pool is formed. Kim and colleagues show data that support epigenetic modifications and antibody-dependent expansion as mechanisms underlying the formation of this memory-like NK cell pool.