Introduction Emerging evidence suggests that vigorous physical activity may be associated with greater cardioprotective and metabolic benefits than moderate physical activity, but this topic requires further study. Furthermore, no longitudinal study has investigated the combined effect of the Mediterranean diet and the intensity of physical activity on mortality and cardiovascular disease.. Objective This study aims to evaluate the long-term relationship betweenthe intensity of physical activity and the risk of developing metabolic syndrome and cardiovascular disease in a prospective cohort study. We also intend to assess the individual and combined effects of adherence to the Mediterranean diet and intensity of physical activity on all-cause mortality and cardiovascular disease. Methods and design The Seguimiento Universidad de Navarra (SUN) Project comprises Spanish university graduates. When evaluating the incidence of metabolic syndrome or cardiovascular disease, we excluded participants with any component of metabolic syndrome or cardiovascular disease prior to study entry. We estimated the mean intensity of leisuretime physical activity using a validated questionnaire. An 8-item score was also constructed to assess an active lifestyle. Adherence to the Mediterranean diet was obtained from a validated 136-item food frequency questionnaire and we used two validated dietary scores. The association between intensity of leisure-time physical activity and metabolic syndrome or cardiovascular disease (myocardial infarction, stroke, and death from cardiovascular causes) was evaluated with logistic regression models or Cox proportional hazards models respectively, adjusting for total energy expenditure and other confounding factors. In addition, multivariable Cox regression models were used to study the individual and combined effect of adherence to the Mediterranean diet, intensity of physical activity, and an active lifestyle on all-cause mortality and cardiovascular disease. 4 Results Among 10,145 participants without any criteria for metabolic syndrome, 412 new cases of metabolic syndrome were observed. Vigorous physical activity was associated with a 37% relatively lower risk (Adjusted OR=0.63, 95% CI=0.44, 0.89) compared with light activity, independent of the total energy expenditure and with a linear trend. During 172,299 person-years of follow-up, we recorded 127 cases of cardiovascular disease. Vigorous physical activity was associated with a 69% relatively lower risk (Adjusted HR=0.31, 95% CI=0.12, 0.79) compared with inactivity, independent of the total energy expenditure and with a linear trend. During a median follow-up of 10.3 years, we recorded 305 deaths. Participants with an active lifestyle and greater adherence to the Mediterranean diet had lower mortality (adjusted HR=0.39, 95% CI=0.21, 0.72), and when intensity was added to this combination, its power protective was even greater (adjusted HR=0.33, 95% CI=0.15, 0.71). Likewise, when analyzing joint exposure to the Mediterranean diet and an active lifestyle or intensity of physical activity, the greatest benefit was related to greater adherence to the Mediterranean diet and a more active lifestyle or vigorous physical activity, respectively. In any case, although there is a synergy, a multiplicative interaction between the Mediterranean diet and the intensity of physical activity was not found. Conclusions In the SUN cohort, given the same level of energy expenditure, respondents who engage in vigorous leisure-time physical activity have a lower risk of developing metabolic syndrome and cardiovascular disease. In the SUN cohort, the combined effect of Mediterranean diet adherence and physical activity intensity had synergistic effects on mortality and cardiovascular disease risk reduction.