OBJECTIVE Guidelines recommend that sepsis be treated with an early resuscitation protocol such as early goal-directed therapy. Our objective was to assess the cost-effectiveness of implementing early goal-directed therapy as a routine protocol. METHODS Prospective before and after study. METHODS Large urban hospital emergency department with >110,000 visits/yr. METHODS The target population was patients with consensus criteria for septic shock. We excluded those with age <18 yrs, no aggressive care desired, or need for immediate surgery. METHODS Clinical and cost data were prospectively collected on two groups: 1) patients from 1 yr before; and 2) 2 yrs after implementing early goal-directed therapy as standard of care. Before phase patients received nonprotocolized care at attending discretion. The primary outcomes were 1-yr mortality, discounted life expectancy, and quality-adjusted life-years. Using costs and quality-adjusted life-years, we constructed an incremental cost-effectiveness ratio and performed a net monetary benefit analysis, producing the probability that the intervention was cost-effective given different values for the willingness to pay for a quality-adjusted life-year. RESULTS Two hundred eighty-five subjects, 79 in the before and 206 in the after phases, were enrolled. Treatment with early goal-directed therapy was associated with an increased hospital cost of $7,028 and an increase in both discounted sepsis-adjusted life expectancy and quality-adjusted life years of 1.5 and 1.3 yrs, respectively. Early goal-directed therapy use was associated with a cost of $5,397 per quality-adjusted life-years gained and the net monetary benefit analysis indicates a 98% probability (p = .038) that early goal-directed therapy is cost-effective at a willingness to pay of $50,000 per quality-adjusted life-years. CONCLUSIONS Implementation of early goal-directed therapy in the emergency department care of patients with severe sepsis is cost-effective.