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To determine the financial impact of a sepsis protocol designed for use in the emergency department.Retrospective analysis of a before-after study testing the implications of sepsis protocol.Academic, tertiary care hospital in the United States.Persons with septic shock presenting to the emergency department.A multifaceted protocol developed from recent scientific literature on sepsis and the Surviving Sepsis Campaign. The protocol emphasized identification of septic patients, aggressive fluid resuscitation, timely antibiotic administration, and appropriateness of antibiotics, along with other adjunctive, supportive measures in sepsis care.We compared patients treated before the protocol with those cared for after the protocol was implemented. Overall hospital costs represented the primary end point, whereas hospital length of stay served as a secondary end point. All hospital costs were calculated based on charges after conversion to costs based on department-specific cost-to-charge ratios. We also attempted to measure the independent impact of the protocol on costs through linear regression. We conducted a sensitivity analysis assessing these end points in the subgroup of subjects who survived their hospitalization. The total cohort included 120 subjects (evenly divided into the before and after cohorts) with a mean age of 64.7 ± 18.2 yrs and median Acute Physiology and Chronic Health Evaluation II score of 22.5 ± 8.3. There were more survivors following the protocol's adoption (70.0% vs. 51.7%, p = .040). Median total costs were significantly lower with use of the protocol ($16,103 vs. $21,985, p = .008). The length of stay was also on average 5 days less among the postintervention population (p = .023). A Cox proportional hazard model indicated that the protocol was independently associated with less per-patient cost. Restricting the analysis to only survivors did not appreciably change our observations.Use of a sepsis protocol can result not only in improved mortality but also in substantial savings for institutions and third party payers. Broader implementation of sepsis treatment protocols represents a potential means for enhancing resource use while containing costs.