- Context: 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. Objective: To assess the cost-effectiveness of an integrated sepsis protocol, as compared with conventional care. Design: 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. Setting: Beth Israel Deaconess Medical Center. Patients: Overall, 79 patients presenting to the emergency department with septic shock in the treatment cohort and 51 patients in the control group. Interventions: 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. Main Outcome Measures: 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. Results: 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. Conclusions: 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.