OBJECTIVES: We sought to describe the various cardiovascular complications that occurred in the Lyon Diet Heart Study (a secondary prevention trial testing the protective effects of a Mediterranean type of diet), to analyze their relations with the associated drug treatments and to gain insights into the possible mechanisms underlying the beneficial effects of certain nutriments. BACKGROUND: Dietary habits are implicated in coronary heart disease, and the traditional Mediterranean diet is thought to be cardioprotective. However, the exact mechanisms of this protection are unknown. METHODS: A total of 605 patients (303 control subjects and 302 study patients) were studied over a mean period of 27 months. Major primary end points (cardiovascular death and nonfatal acute myocardial infarction), secondary end points (including unstable angina, stroke, heart failure and embolisms) and minor end points (stable angina, need for myocardial revascularization, postangioplasty restenosis and thrombophlebitis) were analyzed separately and in combination. RESULTS: When major primary and secondary end points were combined, there were 59 events in control subjects and 14 events in the study patients, showing a risk reduction of 76% (p < 0.0001). When these end points were combined with the minor end points, there were 104 events in control subjects and 68 events in the study patients, giving a risk reduction of 37% (p < 0.005). By observational analysis, only aspirin among the medications appeared to be significantly protective (risk ratio after adjustment for prognosis factors 0.45; 95% confidence interval 0.25 to 0.80). CONCLUSIONS: These data show a protective effect of the Mediterranean diet. However, the risk reduction varied depending on the type of end point considered. Our hypothesis is that different pathogenetic mechanisms were responsible for the development of the various complications. It is likely that certain nutriments characteristic of the Mediterranean diet (omega-3 fatty acids, oleic acid antioxidant vitamins) have specific cardioprotective effects.