Natural Killer (NK) cells differentiate and mature during the human life course; human cytomegalovirus (HCMV) infection is one known driver of this process. We have explored human NK cell phenotypic and functional maturation in a rural African (Gambian) population with a high prevalence of HCMV. The impact of age on the frequency, absolute number, phenotype and functional capacity of NK cells was monitored in 191 individuals aged from 1 to 49 years. Increasing frequencies of NK cells with age were associated with increased proportions of CD56(dim) cells expressing the differentiation marker CD57 and expansion of the NKG2C(+) subset. Frequencies of NK cells responding to exogenous cytokines declined with age in line with a decreased proportion of CD57(-) cells. These changes coincided with a highly significant drop in anti-HCMV IgG titres by the age of 10 years suggesting that HCMV infection is brought under control as NK cells differentiate (or vice versa). Deletion at the NKG2C locus was associated with a gene dose-dependent reduction in proportions of CD94(+) and CD57(+) NK cells. Importantly, anti-HCMV IgG titres were significantly elevated in NKG2C(-/-) children suggesting that lack of expression of NKG2C may be associated with altered control of HCMV in childhood.