BACKGROUND: Hypercholesterolemia has been identified as a major risk factor for the development of coronary artery disease. The aim of this study was to assess the effect of a Mediterranean diet on the development of non-fatal acute coronary syndromes (ACS) in hypercholesterolemic people, with or without statin treatment. METHODS: During 2000-2001, 848 randomly selected patients with a first event of coronary heart disease and 1078 cardiovascular disease-free people, matched to the patients by sex, age and region, were studied. Treatment of hypercholesterolemia with statin and the adoption of a Mediterranean diet were recorded. RESULTS: Hypercholesterolemia was present in 534 (63%) out of 848 coronary patients and 399 (37%) out of 1078 control participants. One hundred and seventy-one (32%) of the hypercholesterolemic patients and 168 (42%) of the hypercholesterolemic control participants were treated with statins and also followed a Mediterranean diet. The analysis showed that the combination of a Mediterranean diet and statin medical therapy is associated with an additional reduction of the coronary risk (odds ratio = 0.57, P < 0.01), independently from cholesterol levels and the other cardiovascular factors. CONCLUSION: The adoption of a Mediterranean diet by hypercholesterolemic people seems to reinforce the benefits from statin treatment on lipid levels and reduces the risk of developing ACS. However, it is hard to claim that our findings suggest causal evidence, and in order to explain the potential common mechanism between diet and statin treatment much remains to be learned.