During mouse cytomegalovirus (CMV) infection, a population of Ly49H + natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response."Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C + NK cells expanded and were potent producers of IFNγ. NKG2C + NK cells predominately expressed killer cell immunoglobulin-like receptor,andself-killer cell immunoglobulin-like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56 dim NK cells. Strikingly, increased frequencies of NKG2C + NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C + NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15RαmRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.