The aim of the present work was to evaluate the association between adherence to the Mediterranean diet and the development of ischemic stroke according to cholesterol levels. During 2009-2010, 500 participants were enrolled; 250 were consecutive patients (77 ± 9 years, 55.6% men) with a first ischemic stroke and 250 population-based, control participants, matched to the patients by age and sex. Sociodemographic, clinical, dietary, and other lifestyle characteristics were measured. Adherence to the Mediterranean diet was assessed by the validated MedDietScore (theoretical range: 0-55). After various adjustments, each 1/55 unit increase in the MedDietScore was associated with 17% lower likelihood of having an ischemic stroke in nonhypercholesterolemic participants (95%CI: 0.72-0.96) and 10% lower likelihood in participants with hypercholesterolemia (95%CI: 0.81-0.99). The present work highlights the cardioprotective benefits from the adoption of the Mediterranean diet, by showing its beneficial effect regarding ischemic stroke development, regardless of the presence of hypercholesterolemia.