The impact of weight loss on cardiovascular disease risk within the frame of the Mediterranean dietary pattern has not yet been tested using a sufficiently large randomized trial (Malik, Hu, 2007). We propose to run a parallel group, multi-center, randomized, primary prevention trial (PREDIMED PLUS) on men aged 55-75 years and women 65-75 years, with a body mass index ≥27 to <40 kg/m2 and meeting at least 3 criteria for the metabolic syndrome. The objective of the present research is to address the cardiovascular effect of an intensive weight-loss lifestyle intervention based on an energy-restricted traditional Mediterranean diet in comparison with a less intensive program using Mediterranean diet, but with no energy restriction, behavioural intervention or physical activity programme. The end-point is a composite of major hard clinical cardiovascular events. We hypothesize that an intensive weight-loss lifestyle intervention, including physical activity, based on the traditional Mediterranean food pattern is a sustainable long-term approach for weight reduction among overweight/obese adults and that the achieved lifestyle changes will exert beneficial effects on cardiovascular disease incidence, according to our experience (Estruch R et al., 2012) and research by other investigators (Shai et al., 2008). The rationale for the proposed investigation is that it can provide a new, affordable, and sustainable approach to reduce excess cardiovascular morbidity and mortality among overweight/obese adults, beyond what was already observed in the PREDIMED I trial.