OBJECTIVES: To determine the cost-effectiveness of the protocol of the international ‘Surviving Sepsis Campaign’ (SSC) for the treatment of severe sepsis in Spain after the implementation of a multicentre educational program compared with the conventional care of severe sepsis. METHODS: Observational prospective before and after study in 59 medical-surgical intensive care units located throughout Spain. A total of 854 patients were enrolled in the pre-educational program cohort (usual or standard care of severe sepsis, November-December 2005) and 1465 patients during the post-educational program (SSC protocol care of severe sepsis, March-June 2006). The educational program aimed to increase the adherence to the SSC protocol. The SSC protocol included pharmacological (antibiotics, fluids, steroids and drotrecogina alfa (activated)) and medical (early-goal directed therapy, tight glucose control and lung protective strategy) interventions. Clinical (hospital mortality) and economical (health care resource and treatment costs) outcomes were recorded. Health care system perspective was used for costs. Incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were used as primary outcomes. ICERs and ICURs were estimated by using multivariable regression models and its variability addressed by using bootstrapping. RESULTS: Patients in the SSC protocol care cohort had a lower risk of hospital mortality (44.0% vs. 39.7%, P=0.04). However, the SSC protocol care resulted in a mean increase in cost of €1800 per patient, largely driven by increased length of stay. Mean life years gained (LYG) and quality-adjusted life years (QALYs) were higher in the SSC protocol care cohort: 0.7 years and 0.5 QALYs, respectively. The adjusted ICER of the SSC protocol was €2556.9 per LYG and the adjusted ICUR was €3579.6 per QALY. Ninety percent of the bootstrap replications were below the threshold of €30,000 per LYG. CONCLUSIONS: The SSC protocol seems to be a cost–effectiveness option for treating severe sepsis in Spain.