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The risk of the acute respiratory distress syndrome (ARDS) is increased in passive and active smokers after blunt trauma. However, the mechanisms responsible, including the role of platelet aggregation, for this association are unknown.We analyzed 215 patients with severe blunt trauma from a prospective observational cohort at a Level I trauma center between 2010 and 2015. Subjects underwent impedance-based platelet aggregometry in response to platelet agonists arachidonic acid, adenosine diphosphate, collagen, and thrombin receptor activating peptide-6. Acute respiratory distress syndrome within the first 8 days of admission was adjudicated using Berlin criteria. Plasma cotinine was measured to assess cigarette smoke exposure. Regression analyses were used to assess the relationship between (1) platelet aggregation and ARDS and (2) cigarette smoke exposure and platelet aggregation.At both 0 hour and 24 hours, impaired platelet aggregation was associated with increased odds of developing ARDS. Cigarette smoke exposure was associated with increased platelet aggregation upon arrival to the emergency department. However, at 24 hours, cigarette smoke exposure was associated with increased impairment in platelet aggregation, reflecting a statistically significant decline in platelet aggregation over the initial 24 hours after trauma. The relationship between this decline in platelet aggregation and ARDS differed by cigarette smoke exposure status, suggesting that impaired platelet activation differentially affects the risk of ARDS in those with cigarette smoke exposure (arachidonic acid, p for interaction: 0.005, collagen p for interaction: 0.02, adenosine diphosphate, p for interaction: 0.05).Impaired platelet aggregation at 0 hour and 24 hours is associated with an increased risk of developing ARDS after severe blunt trauma. Cigarette smoke–exposed patients are more likely to develop impaired platelet aggregation over the first 24 hours of admission, which may contribute to their increased risk of ARDS.Prognostic/Epidemiological, level III.