PREDIMED-PLUS is a multi-centre, randomised, primary prevention trial on men (55-75 years) and women (60-75 years), with body mass index ≥27 to <40 kg/m2 and metabolic syndrome. The intervention is an intensive weight-loss lifestyle program with energy-restricted Mediterranean diet and physical activity in comparison with a less intensive program using Mediterranean diet (without energy restriction or physical activity). The end-point is a composite of major hard clinical cardiovascular events. The final sample size will be 6000 participants (3000 in each group). The recruitment started in September 2013 and will finish in December 2015. The final results will be available in 2020. Effect of an intensive lifestyle intervention with an energy-restricted Mediterranean diet, increased physical activity, and behavioural treatment on the primary prevention of cardiovascular diseases: the PREDIMED-PLUS randomized clinical trial.