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To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome. Despite equivocal results in sepsis trials, anakinra is effective in treating macrophage activation syndrome, a similar entity with fever, disseminated intravascular coagulation, hepatobiliary dysfunction, cytopenias, and hyperferritinemia. Hence, sepsis patients with macrophage activation syndrome features may benefit from interleukin-1 receptor blockade.Reanalysis of deidentified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis.Multicenter study recruiting through 91 centers from 11 countries in Europe and North America.Sepsis patients with multiorgan dysfunction syndrome and/or shock (original study) were regrouped based on the presence or the absence of concurrent hepatobiliary dysfunction and disseminated intravascular coagulation as features of macrophage activation syndrome. The non–hepatobiliary dysfunction/disseminated intravascular coagulation group included patients with only hepatobiliary dysfunction, only disseminated intravascular coagulation, or neither.Treatment with anakinra or placebo.Main outcome was 28–day mortality. Descriptive and comparative statistics were performed. Data were available for 763 adults from the original study cohort, randomized to receive either anakinra or placebo. Concurrent hepatobiliary dysfunction/disseminated intravascular coagulation was noted in 43 patients (5.6% of total; 18–75 years old; 47% women). The 28-day survival was similar in both anakinra and placebo-treated non–hepatobiliary dysfunction/disseminated intravascular coagulation patients (71.4% vs 70.8%; p = 0.88). Treatment with anakinra was associated with significant improvement in the 28-day survival rate in hepatobiliary dysfunction/disseminated intravascular coagulation patients (65.4% anakinra vs 35.3% placebo), with hazard ratio for death 0.28 (0.11–0.71; p = 0.0071) for the treatment group in Cox regression.In this subgroup analysis, interleukin-1 receptor blockade was associated with significant improvement in survival of patients with sepsis and concurrent hepatobiliary dysfunction/disseminated intravascular coagulation. A prospective randomized trial using features of macrophage activation syndrome for mortality risk stratification should be undertaken to confirm the role of interleukin-1 blockage.