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Low doses of acetyl salicylic acid, acting through 15-epi-lipoxin A4, have been shown to be anti-inflammatory in human studies. The manifold effects of acetyl salicylic acid on human physiology potentially may benefit patients with the systemic inflammatory response syndrome after sepsis or tissue trauma. We sought to determine whether acetyl salicylic acid administration at the time of development of systemic inflammatory response syndrome is associated with reduced mortality.Retrospective cohort study of consecutive intensive care unit admissions between April 2000 and November 2009.Australian tertiary referral center.Seven-thousand nine-hundred forty-five intensive care unit admissions examined.The probability of in-hospital death during admissions in which individuals were identified as having systemic inflammatory response syndrome or sepsis was analyzed according to whether they were administered acetyl salicylic acid. Propensity analysis that matched all patients for their probability of being prescribed acetyl salicylic acid was undertaken. Among 5523 patients with a first episode of systemic inflammatory response syndrome, 2082 were administered acetyl salicylic acid in a 24-hr period around the time of systemic inflammatory response syndrome recognition. Propensity analysis showed a 10.9% mortality for acetyl salicylic acid users and 17.2% mortality in the propensity-matched nonusers (absolute risk difference –6.2%; 95% confidence interval –9.5% to –3.5%). Propensity matching also found that acetyl salicylic acid administration was associated with increased risk of renal injury (6.2% vs. 2.9%; absolute risk difference 13.3%; 95% confidence interval 2.5% to 5.0%). In the 970 patients with proven sepsis, acetyl salicylic acid administration was associated with a lower mortality (27.4% vs. 42.2%; absolute risk difference –14.8%; 95% confidence interval –18.9% to –8.6%) after propensity matching. This quasi-experimental study cannot establish a causal association between acetyl salicylic acid and death from systemic inflammatory response syndrome or sepsis. Unrecognized confounders may remain but numerous covariates are included in the analyses.Our study shows a strong association between acetyl salicylic acid and survival in intensive care unit systemic inflammatory response syndrome and sepsis patients. The effect of acetyl salicylic acid treatment on mortality of patients with systemic inflammatory response syndrome and sepsis needs to be evaluated with prospective randomized intervention studies.