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Consumption of a traditional Mediterranean diet and n-3 polyunsaturated fatty acids (PUFAs) was shown to be effective in reducing the complications of coronary heart disease in randomised controlled trials. Epidemiological studies and controlled trials indicate that plant- and sea-derived n-3 PUFAs are likely to be important mediators of the protection provided by traditional Mediterranean diets. Of note, consumption of marine n-3 PUFAs from fish and other seafood is high in certain Mediterranean countries (Spain, Portugal), but quite low in others (Italy, Greece). A relative insufficiency of dietary marine n-3 PUFAs among Italians might in part explain the results of the GISSI-Prevenzione trial, in which a modest supplementation of eicosapentaenoic acid + docosahexaenoic acid (∼850 mg/day) produced striking reductions in coronary heart disease death (−30%) and sudden cardiac death (−45%) among patients with known heart disease. The protection provided by n-3 PUFAs from both plant and marine sources may be partly dependent on other dietary factors. Plant and marine n-3 PUFAs are likely to be major mediators of the protective effect provided by traditional Mediterranean diets.