ABSTRACTBackgroundDrug–drug interactions (DDIs), highly prevalent amongst the elderly, can lead to avoidable medication‐related harm. Cardiovascular and central nervous system (CNS) drugs are commonly implicated. To date, there is no consensus on how to measure DDIs, making comparisons across countries challenging.ObjectiveTo (i) establish a common data model (CDM) to measure DDI prevalence in the older (aged ≥ 70 years) community‐dwelling population of three European countries and (ii) compare and describe cardiovascular and CNS DDI prevalence rates across these countries.MethodsThis cross‐country study will apply a harmonised method of DDI identification and analysis using the WHO ATC classification system and national pharmacy claims data from three European countries (Ireland, Italy, Spain). Patients aged ≥ 70 years dispensed ≥ 2 medications during 2016 will be identified from each country's national database. ‘Severe’ cardiovascular and CNS DDIs (i.e., may result in a life‐threatening event/permanent detrimental effect) will be identified using the British National Formulary and Stockley's Drug Interactions. Two separate lists of ‘severe’ DDIs, per medications reimbursed, will be applied to each database: (i) DDIs relevant to each individual country and (ii) DDIs relevant to all three countries. DDIs will be defined as co‐dispensed (same day) and concomitantly (±7 days) dispensed.ResultsDescriptive statistics, including DDI prevalence and 95% confidence intervals, will be reported for each country. Prevalence will be pooled and compared across countries using random effects models and meta‐regression, where feasible.ConclusionThe EuroDDI study will develop a harmonised method to measure and compare DDI prevalence across health‐related databases in Europe.