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Neutrophils play a crucial role in defense against systemic candidiasis, a disease associated with a high mortality rate in patients receiving immunosuppressive therapy, although the early immune mechanisms that boost the candidacidal activity of neutrophils remain to be defined in depth. Here, we used a murine model of systemic candidiasis to explore the role of inflammatory Ly6Chigh monocytes in NK cell-mediated neutrophil activation during the innate immune response against C. albicans. We found that efficient anti-Candida immunity required a collaborative response between the spleen and kidney, which relied on type I interferon-dependent IL-15 production by spleen inflammatory Ly6Chigh monocytes to drive efficient activation and GM-CSF release by spleen NK cells; this in turn was necessary to boost the Candida killing potential of kidney neutrophils. Our findings unveil a role for IL-15 as a critical mediator in defense against systemic candidiasis and hold promise for the design of IL-15-based antifungal immunotherapies.NK cell and neutrophil activation during C. albicans infection requires IL-15Inflammatory Ly6Chigh monocytes are the main source of IL-15 in response to C. albicans infectionType I IFN controls C. albicans-induced IL-15 production by inflammatory monocytesDefense against systemic candidiasis requires spleen-kidney cooperative immunityThe kidney is the main target organ in systemic C. albicans infection. Domínguez-Andrés et al. now show that effective defense against systemic candidiasis relies on type I interferon-dependent IL-15 production by spleen inflammatory monocytes, which drives splenic NK cell activation and GM-CSF release that in turn boost the candidacidal potential of kidney neutrophils.