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Sepsis is a lethal syndrome annually affecting approximately 900,000 patients in the United States alone. Despite their benefit in rheumatoid disease, selective antitumor necrosis factor agents failed to improve outcome in early sepsis trials in the 1990s. However, data from additional sepsis trials testing these agents are now available. We therefore sought to determine the effect on survival of selective antitumor necrosis factor agents in randomized clinical sepsis trials..PubMed, Scopus, Embase, and Web of Science.Randomized human sepsis trials of selective antitumor necrosis factor agents reporting survival rates.Two investigators independently collected relevant data on study characteristics, treatment interventions, and patients from each study.Antitumor necrosis factor agents in 15 sepsis trials (n = 8,896 patients) meeting inclusion criteria had similar effects (I2 = 0, p = 0.84) and compared with controls (placebo in 14 trials or a lower dose in one trial) overall decreased the relative risk of death (95% CI) (0.93 [0.88–0.98], p = 0.01). In subgroup analysis, tumor necrosis factor monoclonal antibodies (10 trials, n = 6,818) alone produced a significant survival benefit (0.93 [0.87, 0.99], p = 0.02) (I2 = 0, p = 0.83). Tumor necrosis factor polyclonal antibodies (two trials, n = 151) and low-molecular-weight soluble receptor (two trials, n = 1,786) had similar beneficial effects to antitumor necrosis factor agents overall (0.82 [0.49–1.37], p = 0.45; 0.93 [0.81–1.08], p = 0.33, respectively). The effect of tumor necrosis factor high-molecular-weight soluble receptor (one trial, n = 141) was not significantly different from other agents but was on the side of harm (1.50 [0.86–2.61], p = 0.16).Antitumor necrosis factor agents produced a modest but significant decrease in the risk of dying with sepsis. Prior individual trials failed to demonstrate benefit, likely because they were underpowered. A definitive trial demonstrating the potential benefit of such agents might require 10,000 or more patients with sepsis.