OBJECTIVES: Determine which new generation proton pump inhibitor (PPI) is most cost-effective in the treatment of GERD after omeprazole failure as well as their expected impact on Spanish NHS budget. METHODS: A pharmacoeconomic deterministic model was developed, based on data extracted from literature, form an NHS perspective to compare esomeprazole (ESO40mg/d), lansoprazole (LANSO30mg/d), pantoprazole (PANTO40mg/d) and rabeprazole (RABE20mg/d) in patients with GERD refractory to omeprazole (patients without remission or remaining symptomatic after OME 20mg/day 4 weeks). The effectiveness measure was symptom free-days after 12 months of treatment. The costs included were drugs and health care utilization resources (diagnostic methods, physicians visits and surgery), expressed as 2006 €. Moreover a budget impact model was done to know the affordability of most cost-effective drug utilization in a 1,000 patients cohort. RESULTS: ESO provide higher remission rates (238 days without symptoms) than the other alternatives: LANSO-213 days; PANTO-203 days; RABE-205 days. The annual cost by patient are: 652€-ESO, 703€-LANSO, 734€-PANTO; 706€-RABE. The analysis indicates that ESO being a dominant therapy in this case. The expected cost by patient is 428.84€ (310 symptoms free-days), based on 2006 treatment patterns. Increasing the ESO utilization on 25, 50, 75 & 100%, instead of less effective and costly drugs, could produce potential savings for the Spanish NHS: 720€, 1430€, 2000€ & 2860€, respectively; which would allow for the treatment of more patients with the same budget: 1.68, 3.35, 4.69 and 6.71 additional patients, correspondingly. CONCLUSION: ESO is the most cost-effective and efficient PPI in the treatment of GERD after omeprazole failure in Spain.