The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5-20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage . Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19 . NK cells contribute to early phases of virus control and to the regulation of adaptive responses . The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover . We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19 . Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and``memory"KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules . Impaired cytotoxicity and IFN-Î³ production were associated with conserved expression of natural cytotoxicity receptors and perforin . Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells . Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells . Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration . Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches.