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Background/Purpose: Macrophage Activation Syndrome (MAS) is a life-threatening systemic inflammatory disorder of unknown etiology. While MAS has no known genetic basis, clinical similarity with a genetic disorder of impaired cytotoxicity known as primary Hemophagocytic Lymphohistiocytosis (HLH) has suggested shared pathogenesis. In contrast, other investigations have suggested innate immune dysregulation drives MAS. Methods: We performed detailed clinical, genetic, and immunologic evaluation of a patient with early onset, recurrent MAS-like disease including whole exome sequencing and analyses of serum cytokines, whole blood transcription, and stimulated monocyte and macrophage responses. We subsequently tested the effects of a de novo mutation in transfection experiments with a monocytic cell line. Results: We identified a 7 year-old female with recurrent episodes of fever, splenomegaly, transaminitis, pancytopenia, occasional evanescent rash, and massive hyperferritinemia since 6 months of age. Her Natural Killer cell function was normal, and she had no mutations in genes associated with HLH or hereditary periodic fever syndromes. Whole exome sequencing identified a de novo missense mutation in a highly conserved area in the nucleotide-binding region of the inflammasome component NLRC4. Interleukin (IL)-1b, Interferon a2, and particularly IL-18 were elevated in the patient's peripheral blood even during clinical quiescence. The patient's monocytes produced more of a number of inflammatory cytokines in response to stimulation than controls, while monocyte-derived macrophages specifically over-produced IL-1b and IL-18. Transfection of THP1 monocytes with a plasmid bearing a mutant NLRC4 construct resulted in increased cell death and IL-1b production versus a wild-type plasmid. The patient showed short-term clinical improvement and ability to wean steroids with recombinant IL-1 receptor antagonist (IL-1ra) therapy. Conclusion: While NLRP3 inflammasome hyperactivity has been implicated in the pathogenesis of a variety of autoinflammatory conditions, our data suggest that a mutation in the ADP binding domain of NLRC4 can result in MAS-like disease. This mutation may destabilize NLRC4's auto-inhibited conformation by altering ADP binding (), resulting in enhanced/spontaneous activation and pathogenic production of IL-1b and IL-18. NLRC4 hyperactivity represents a novel mechanism of MAS/HLH pathogenesis. [ABSTRACT FROM AUTHOR]