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Sepsis is associated with high mortality and treatment costs. International guidelines recommend the implementation of integrated sepsis protocols; however, the true cost and cost-effectiveness of these are unknown.To assess the cost-effectiveness of an integrated sepsis protocol, as compared with conventional care.Prospective cohort study of consecutive patients presenting with septic shock and enrolled in the institution's integrated sepsis protocol. Clinical and economic outcomes were compared with a historical control cohort.Beth Israel Deaconess Medical Center.Overall, 79 patients presenting to the emergency department with septic shock in the treatment cohort and 51 patients in the control group.An integrated sepsis treatment protocol incorporating empirical antibiotics, early goal-directed therapy, intensive insulin therapy, lung-protective ventilation, and consideration for drotrecogin alfa and steroid therapy.In-hospital treatment costs were collected using the hospital's detailed accounting system. The cost-effectiveness analysis was performed from the perspective of the healthcare system using a lifetime horizon. The primary end point for the cost-effectiveness analysis was the incremental cost per quality-adjusted life year gained.Mortality in the treatment group was 20.3% vs. 29.4% in the control group (p = .23). Implementing an integrated sepsis protocol resulted in a mean increase in cost of ∼$8,800 per patient, largely driven by increased intensive care unit length of stay. Life expectancy and quality-adjusted life years were higher in the treatment group; 0.78 and 0.54, respectively. The protocol was associated with an incremental cost of $11,274 per life-year saved and a cost of $16,309 per quality-adjusted life year gained.In patients with septic shock, an integrated sepsis protocol, although not cost-saving, appears to be cost-effective and compares very favorably to other commonly delivered acute care interventions.