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Background and aims A Mediterranean diet has been associated with lower all-cause and cardiovascular disease (CVD) morbidity and mortality, but the clinical and behavioral pathway has not been well understood and appreciated. The aim of this work was to explore the path between adherence to a Mediterranean-type diet, lifestyle behaviors, clinical status, and a 10-year incidence of CVD. Methods and results The ATTICA study was carried out in the Athens area during 2001–2002 and included 3042 participants free of CVD at baseline (49.8% men, aged 18–89). Adherence to a Mediterranean diet was assessed using the MedDietScore (range 0–55). During 2011–2012, 2583 out of the 3042 participants were found during the 10-year follow-up (15% lost to follow-up). Adherence to a Mediterranean diet decreased CVD risk (relative Risk (RR) per 1/55 unit = 0.96, 95% confidence interval (CI): 0.93, 1.00), independently of various sociodemographic, lifestyle, and clinical factors. Subgroup analyses revealed that participants with an unhealthy lifestyle (i.e., smokers, and obese and sedentary persons) remained protected from CVD through a greater adherence to a Mediterranean diet (RR for smokers = 0.92, 95%CI: 0.88, 0.97; RR for obese participants = 0.90, 95%CI: 0.82, 0.979; and RR for sedentary participants = 0.95, 95%CI: 0.90, 0.99). Path analysis revealed that adherence to a Mediterranean diet not only decreases the levels of C-reactive protein and interleukin-6 but also has an independent protective role against CVD risk per se (total effect of the MedDietScore on CVD = −0.003, 95%CI: −0.005 to 0.000). Conclusion Adherence to a Mediterranean diet confers a considerable reduction on CVD risk, independent of various factors. Therefore, even subjects with unhealthy lifestyle behaviors may benefit from adherence to this diet, suggesting another dimension to prevention strategies. [ABSTRACT FROM AUTHOR]