Necroptosis, a form of programmed cell death mediated by receptor interacting serine/threonine-protein kinase-3 (RIPK3), is implicated in murine models of acute respiratory distress syndrome (ARDS). We hypothesized that plasma RIPK3 concentrations in sepsis and trauma would be associated with ARDS development and that plasma RIPK3 would reflect changes in lung tissue RIPK3 in a murine model of systemic inflammation. We utilized prospective cohort studies of critically ill sepsis (n=120) and trauma (n=180) patients and measured plasma RIPK3 at presentation and 48h. Patients were followed for 6days for ARDS by the Berlin definition. We used multivariable logistic regression to determine the association of plasma RIPK3 with ARDS in each cohort, adjusting for confounders. In mice, we determined whether plasma and lung tissue RIPK3 levels rise concomitantly 4h after injection with lipopolysaccharide and ZVAD-FMK, an apoptosis inhibitor. The change in plasma RIPK3 from presentation to 48h (RIPK3) was associated with ARDS in sepsis (OR 1.30, 95% CI 1.03-1.63, per standard deviation) and trauma (OR 1.79, 95% CI 1.33-2.40). This association was not evident for presentation RIPK3 levels. Secondary analyses showed similar findings for the association of RIPK3 with acute kidney injury and 30-day mortality. Mice injected with lipopolysaccharide and ZVAD-FMK had significantly higher plasma (p<0.001) and lung (p=0.005) RIPK3 than control mice. The change in plasma RIPK3 from presentation to 48h in both sepsis and trauma patients is independently associated with ARDS, and plasma RIPK3 may reflect RIPK3 activity in lung tissue.