Context: Severe sepsis is associated with high mortality and increased costs. The 'Surviving Sepsis Campaign' (SSC) protocol was developed as an international initiative to reduce mortality. However, its cost-effectiveness is unknown. Objective: To determine the costeffectiveness of the SSC protocol for the treatment of severe sepsis in Spain after the implementation of an educational program compared with the conventional care of severe sepsis. Design: Observational prospective before-and-after study. Setting: 59 medical-surgical intensive care units located throughout Spain. Patients: A total of 854 patients were enrolled in the pre-educational program cohort (usual or standard care of severe sepsis) and 1,465 patients in the posteducational program cohort (SSC protocol care of severe sepsis). Interventions: The educational program aimed to increase adherence to the SSC protocol. The SSC protocol included pharmacological and medical interventions. Main outcome measures: Clinical (hospital mortality) and economic (health-care resource and treatment costs) outcomes were recorded. A health-care system perspective was used for costs. The primary outcome was incremental cost-effectiveness ratio (ICER). Results: Patients in the SSC protocol care cohort had a lower risk of hospital mortality (44.0% vs. 39.7%, P = 0.04). However, mean costs per patient were 1,736 euros higher in the SSC protocol care cohort (95% CI 114-3,358 euros), largely as a result of increased length of stay. Mean life years gained (LYG) were higher in the SSC protocol care cohort: 0.54 years (95% CI 0.02-1.05 years). The adjusted ICER of the SSC protocol was 4,435 euros per LYG. Nearly all (96.5%) the bootstrap replications were below the threshold of 30,000 euros per LYG. Conclusion: The SSC protocol seems to be a cost-effective option for treating severe sepsis in Spain.