We evaluated the role of a Mediterranean-style diet in preventing acute coronary syndromes (ACS). Data from CARDIO2000, a multi-centre retrospective case-control study investigating the association between ACS and demographic, nutritional, lifestyle and medical risk factors were used. We studied 661 patients hospitalized for a first ACS event and 661 matched controls without clinical suspicion of cardiovascular disease. The Mediterranean diet significantly reduced (by 16%) the risk of developing ACS. The association remained significant in the presence of hypertension, hypercholesterolaemia, sedentary lifestyle, diabetes mellitus or a combination of two of these cardiovascular risk factors. Our findings illustrate the importance of the Mediterranean diet in the primary prevention of acute coronary events.