ObjectiveAberrant pyrin inflammasome activity triggers familial Mediterranean fever (FMF) pathogenesis, but the exact mechanism remains elusive and an obstacle to efficient treatment. We undertook this study to identify pyrin inflammasome–specific mechanisms to improve FMF treatment and diagnostics in the future.MethodsPyrin‐specific protein secretion was assessed by proteome analysis in U937‐derived macrophages, and specific findings were confirmed in pyrin inflammasome–activated monocytes from healthy blood donors and patients with FMF, stratified according to MEFV genotype categories corresponding to a suspected increase in FMF disease severity.ResultsProteome data revealed a differential secretion pattern of interleukin‐1 receptor antagonist (IL‐1Ra) from pyrin‐ and NLRP3‐activated U937‐derived macrophages, which was verified by enzyme‐linked immunosorbent assay and quantitative polymerase chain reaction. Moreover, pyrin activation significantly reduced IL1RN messenger RNA expression (P < 0.001) and IL‐1Ra secretion (P < 0.01) in healthy donor and FMF monocytes, respectively. Independent of MEFV genotype, unstimulated FMF monocytes from colchicine‐treated patients secreted lower amounts of IL‐1Ra compared to healthy donors (P < 0.05) and displayed decreased ratios of IL‐1Ra:IL‐1β (P < 0.05), suggesting a reduced antiinflammatory capacity.ConclusionOur data show an inherent lack of IL‐1Ra expression specific to pyrin inflammasome activation, suggesting a new mechanism underlying FMF pathogenesis. The reduced IL‐1Ra levels in FMF monocytes suggest a diminished antiinflammatory capacity that potentially leaves FMF patients sensitive to proinflammatory stimuli, regardless of receiving colchicine therapy. Thus, considering the potential clinical consequence of reduced monocyte IL‐1Ra secretion in FMF patients, we suggest further investigation into IL‐1Ra dynamics and its potential implications for FMF treatment in the future.