OBJECTIVE: We evaluated the interaction between adherence to the Mediterranean diet and region of Greece on the likelihood of having acute coronary syndromes (ACS). METHODS: During 2000-2001, a random sample of 848 patients (61+/-10 years) with their first coronary heart disease event, and 1078 frequency matched (by age-sex) controls with no cardiovascular disease in their medical history, from all the country, entered into the study. Among several factors, adherence to the Mediterranean diet was assessed by a diet-score that incorporated the inherent characteristics of this diet. RESULTS: The multi-adjusted analysis showed that a 10-unit increase in the diet score was associated with a 27% (95% CI 0.66 to 0.89) decrease of the odds of having ACS. Moreover, a highly significant interaction was observed between region and diet score (p<0.001). The odds ratios varied from roughly 0.5 in Southern to 1.2 or more in Northern Greek regions (p for heterogeneity<0.05). Differences in food patterns consumed did not explain the previous findings. In addition, when we stratified our analysis by rural and urban areas we found significant differences in the estimated odds ratios (p for interaction between diet score and area=0.01), since a 10-unit increase in the diet score was associated with 22% (95% CI 0.63 to 0.96) lower odds n urban areas and 31% (95% CI 0.48 to 0.98) lower odds in rural areas. CONCLUSION: Our findings underline the significance of the Mediterranean diet on the primary prevention of ACS. Moreover, we revealed a geographical variation in the importance of this dietary pattern on coronary risk, independent from the composition of food patterns followed and the prevalence of the common cardiovascular risk factors.