BACKGROUND: Although the role of Mediterranean diet on cardiovascular disease prevention has long been evaluated and understood, its association with the development of stroke has been rarely examined. The aim of the present work was to comparatively evaluate the association between adherence to the Mediterranean diet and the development of an acute coronary syndrome (ACS) or ischemic stroke. METHODS: During the period from 2009 to 2010, 1,000 participants were enrolled; 250 were consecutive patients with a first ACS, 250 were consecutive patients with a first ischemic stroke, and 500 population-based, control subjects, 1-for-1 matched to the patients by age and sex. Sociodemographic, clinical, psychological, dietary, and other lifestyle characteristics were measured. Adherence to the Mediterranean diet was assessed by the validated MedDietScore (theoretical range 0-55). RESULTS: After various adjustments were made, it was observed that for each 1-of-55-unit increase of the MedDietScore, the corresponding odds ratio for having an ACS was 0.91 (95% CI 0.87-0.96), whereas regarding stroke, it was 0.88 (95% CI 0.82-0.94). CONCLUSIONS: The present work extended the current knowledge about the cardioprotective benefits from the adoption of the Mediterranean diet by showing an additional protective effect on ischemic stroke development.