OBJECTIVES: Pharmaceutical spending control is a major objective for most governments. The introduction of new drugs is considered a reason for increased spending, although often leading to actual savings. This study aims to evaluate the effect that market penetration of esomeprazole (Nexium) will have on PPI pharmaceutical expenditures in Greece. METHODS: A model estimating drug budget savings potentially achieved by replacing other PPIs with Nexium in the Greek market has been developed based on clinical trial results and market research data. This model is based on current (MAT/5/2001) PPI sales data (IMS data). For every marketed PPI, a “replacement ratio” for each PPI according to indication is calculated. Then, a “market penetration percentage” for Nexium is estimated for a period of three years for every dosage form and indication. Overall PPI costs with or without Nexium are calculated for the Greek population according to indication. The overall cost difference depicts potential cost savings. RESULTS: The predicted Greek annual expenditure in public prices for PPIs without Nexium is approximately GRD 27.2 billion. In indications which lead to expenditures of GRD 23 billion Nexium could be prescribed leading to a potential reduction in PPI costs of approximately 15% of the predicted expenditure without Nexium. Percentage cost-savings are higher if Nexium replaces certain PPIs, like branded omeprazole and pantoprazole. It can be seen that the expected expenditures after Nexium are lower than current costs for all PPIs. This holds across all doses for each of the PPIs. A proportional reduction is expected in overall units sold, measured in 28–pack equivalents. Sensitivity analyses based on varying penetration rates do not alter initial results significantly. CONCLUSION: Nexium offers a disease management approach leading to actual cost savings in PPI expenditures in Greece. The saving impact is greater if highly priced PPIs are replaced.