Background and aims: A healthy lifestyle is essential to prevent cardiovascular disease (CVD). However, beyond dietary habits, there is a scarcity of studies comprehensively assessing the typical traditional Mediterranean lifestyle with a multi-dimensional index. We assessed the association between the Mediterranean lifestyle (measured with the MEDLIFE index including diet, physical activity, and other lifestyle factors) and the incidence of CVD. Methods and results: The "Seguimiento Universidad de Navarra" (SUN) project is a prospective, dynamic and multipurpose cohort of Spanish university graduates. We calculated a MEDLIFE score, composed of 28 items on food consumption, dietary habits, physical activity, rest, social habits, and conviviality, for 18,631 participants by assigning 1 point for each typical Mediterranean lifestyle factor achieved, for a theoretically possible final score ranging from 0 to 28 points. During an average follow-up of 11.5 years, 172 CVD cases (myocardial infarction, stroke or cardiovascular death) were observed. An inverse association between the MEDLIFE score and the risk of primary cardiovascular events was observed, with multivariable-adjusted hazard ratio (HR) = 0.50; (95% confidence interval, 0.31-0.81) for the highest MEDLIFE scores (14-23 points) compared to the lowest scores (0-9 points), p (trend) = 0.004. Conclusion: A higher level of adherence to the Mediterranean lifestyle was significantly associated with a lower risk of CVD in a Spanish cohort. Public health strategies should promote the Mediterranean lifestyle to preserve cardiovascular health. (c) 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.