OBJECTIVES: The analysis aimed to evaluate the evolution of the national and regional public expenditure regarding Proton Pump Inhibitors (PPIs) in Italy, in relation to national and regional policies. METHODS: The analysis combined data published by the Italian Medicines Agency (AIFA) and Regions and regional and national laws, to understand the impact of the applied policies on PPIs expenditure. RESULTS: Over the past ten years, PPIs consumption increased by 280% (around 14% yearly), with lansoprazole reaching +533%. The number of patients ≥ 18 treatable with PPIs in 2013 was 2.873.500 (6% of adult population), being the first class in terms of expenditure with a per capita value of 15.2€ and consumptions of 74 DDD/1.000 inh./die. Consumptions and expenditure incresed by respectively 6.5% and 1.6% vs 2012. AIFA also highlighted a trend to prescriptive inappropiateness over the years, where the 46.5% of patients do not meet the reimbursability criteria by law. At regional level, Regions have issued a number of regional laws to contain both consumptions and expenditure (e.g. through reference pricing or guidelines to encourage the prescription of genericated drugs), identifying specific performance indicators and target values. We estimated potential savings from the correct application of the reimburability criteria amounting to 260 million €/year, if Regions were able to control prescriptive appropriateness, to which additional savings could be added through focused cost-containment measures. CONCLUSIONS: Despite a number of efforts at both central and regional level, the trend towards inappropriateness and expenditure increase of PPIs is confirmed. A review of both national and regional policies on PPIs expenditure is key to reduce the current waste of economic resources and, with a stable total budget, guarantee additional funding for innovation.