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.