Natural killer (NK) cells are innate immune cells that have been suggested important for control of human cytomegalovirus (HCMV) – an important pathogen in immune suppressed transplant patients. In HCMV seropositive individuals a population of NK cells with adaptive features can expand in peripheral blood and has been shown to have enhanced antiviral function. This is particularly evident following solid organ transplant (SOT) where patients frequently experience episodes of HCMV viremia. In contrast, much less is understood about the identity and function of tissue-resident immune cells in the context of HCMV infection and pathogenesis. In this study, access to tissue-resident immune cells from human organs destined for transplant has enabled us to address this, for the first time. Here we show that human liver-resident (lrNK), like circulating NK (cNK) cells, express increased adaptive markers in HCMV+ individuals. Interestingly, lrNK demonstrated better control of HCMV replication in vitro when compared to cNK cells isolated from the same donor. Furthermore, this control phenotype was elevated if the cells were isolated from HCMV seropositive donors. Crucially, because these studies were performed on perfusates from livers destined for transplantation we could correlate a donor’s lrNK ability to control HCMV in vitro with a reduction in HCMV viraemia in liver transplant recipients in vivo. Finally, we demonstrate that a population of CD2+ NK cells are enriched in patients who did not develop viraemia post-transplant and that loss of control in vitro occurs when CD2 NK cells are depleted or inhibited with anti-CD2 antibodies. Therefore, lrNK have anti-viral activity that could be important for control of HCMV replication in tissue and contribute to better clinical outcomes following organ transplant. Understanding the importance of CD2 expressing populations could have implications for the development of novel therapies aimed at mobilising specific NK cell functions against infections and/or decreasing the ability of HCMV to evade NK responses.