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Natural killer (NK) cells are important in innate immune responses to bacterial and viral pathogens. HIV-1 infection is associated with opportunistic bacterial infections and with microbial translocation, but the nature of the NK cell response to bacteria during HIV-1 infection has not been studied extensively. The objective of this study was to compare NK cell responses to bacteria in HIV-1-infected versus that in uninfected individuals.Multicolor flow cytometry was used to evaluate the ability of blood NK cell subsets (CD56+CD16−, CD56+CD16+, and CD56−CD16+) from treated, virally suppressed, and untreated viremic subjects with chronic HIV-1 infection and uninfected controls, to secrete interferon gamma (IFN-γ) in response to the in vitro stimulation of peripheral blood mononuclear cells with heat-killed commensal Escherichia coli or pathogenic Salmonella typhimurium.All 3 NK cell subsets produced IFN-γ in response to bacteria, but CD56−CD16+ NK cells were least responsive. Untreated HIV-1–infected donors had increased frequencies of CD56−CD16+ NK cells and lower overall frequencies of IFN-γ–producing NK cells responding to E. coli and S. typhimurium than did NK cells from uninfected donors. These NK cell defects were not fully restored in antiretroviral therapy–treated donors. Monocytes were necessary for NK cells to respond to bacteria, but the HIV-associated defect was intrinsic to NK cells because the addition of normal monocytes did not restore IFN-γ production in response to bacteria.Functional defects and numeric alterations of NK cell subsets lead to decreased frequencies of bacteria-reactive, IFN-γ–producing NK cells in HIV-1–infected subjects, even those on antiretroviral therapy.