The PREDIMED (Prevención con Dieta Mediterránea) study was designed to assess the long-term effects of the Mediterranean diet (MeDiet) without any energy restriction on incident cardiovascular disease (CVD) as a multicenter, randomized, primary prevention trial in individuals at high risk. Participants were randomly assigned to 3 diet groups: 1) MeDiet supplemented with extra-virgin olive oil (EVOO); 2) MeDiet supplemented with nuts; and 3) control diet (advice on a low-fat diet). After 4.8 y, 288 major CVD events occurred in 7447 participants; crude hazard ratios were 0.70 (95% CI: 0.53, 0.91) for the MeDiet + EVOO and 0.70 (95% CI: 0.53, 0.94) for the MeDiet + nuts compared with the control group. Respective hazard ratios for incident diabetes (273 cases) among 3541 participants without diabetes were 0.60 (95% CI: 0.43, 0.85) and 0.82 (95% CI: 0.61, 1.10) compared with the control group. After 1-y follow-up, participants in the MeDiet + nuts group showed a significant 13.7% reduction in prevalence of metabolic syndrome compared with reductions of 6.7% and 2.0% in the MeDiet + EVOO and control groups, respectively. Analyses of intermediate markers of cardiovascular risk demonstrated beneficial effects of the MeDiets on blood pressure, lipid profiles, lipoprotein particles, inflammation, oxidative stress, and carotid atherosclerosis, as well as on the expression of proatherogenic genes involved in vascular events and thrombosis. Nutritional genomics studies demonstrated interactions between a MeDiet and cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), apolipoprotein A2 (APOA2), cholesteryl ester transfer protein plasma (CETP), and transcription factor 7-like 2 (TCF7L2) gene polymorphisms. The PREDIMED study results demonstrate that a high-unsaturated fat and antioxidant-rich dietary pattern such as the MeDiet is a useful tool in the prevention of CVD.