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We sought to explore potential mechanisms underlying hospital sepsis case volume-mortality associations by investigating implementation of evidence-based processes of care.Retrospective cohort study. We determined associations of sepsis case volume with three evidence-based processes of care (lactate measurement during first hospital day, norepinephrine as first vasopressor, and avoidance of starch-based colloids) and assessed their role in mediation of case volume-mortality associations.Enhanced administrative data (Premier, Charlotte, NC) from 534 U.S. hospitals.A total of 287,914 adult patients with sepsis present at admission between July 2010 and December 2012 of whom 58,045 received a vasopressor for septic shock during the first 2 days of hospitalization.None.Among patients with sepsis, 1.9% received starch, and among patients with septic shock, 68.3% had lactate measured and 64% received norepinephrine as initial vasopressor. Patients at hospitals with the highest case volume were more likely to have lactate measured (adjusted odds ratio quartile 4 vs quartile 1, 2.8; 95% CI, 2.1–3.7) and receive norepinephrine as initial vasopressor (adjusted odds ratio quartile 4 vs quartile 1, 2.1; 95% CI, 1.6–2.7). Case volume was not associated with avoidance of starch products (adjusted odds ratio quartile 4 vs quartile 1, 0.73; 95% CI, 0.45–1.2). Adherence to evidence-based care was associated with lower hospital mortality (adjusted odds ratio, 0.81; 95% CI, 0.70–0.94) but did not strongly mediate case volume-mortality associations (point estimate change ≤ 2%).In a large cohort of U.S. patients with sepsis, select evidence-based processes of care were more likely implemented at high-volume hospitals but did not strongly mediate case volume-mortality associations. Considering processes and case volume when regionalizing sepsis care may maximize patient outcomes.