Purpose To assess the association between a multi-dimensional Macronutrient Quality Index (MQI) and the risk of cardiovascular disease (CVD) in a Mediterranean cohort. Methods Prospective analyses among 18,418 participants (mean age 36 years, 60.8% women) of the Seguimiento Universidad de Navarra (SUN) cohort. Dietary intake information was obtained through a validated semi-quantitative food-frequency questionnaire (FFQ). The MQI (expressing high-quality macronutrient intake) was calculated based on three previously reported quality indices: the Carbohydrate Quality Index (CQI), the Fat Quality Index (FQI), and the Healthy Plate Protein source Quality Index (HPPQI). Adherence to the Mediterranean diet (MedDiet) and Provegetarian Diet was evaluated using the Trichopoulou index and the score proposed by Martinez-Gonzalez, respectively. CVD was defined as new-onset stroke, myocardial infarction, or CVD death. Results After a median follow-up time of 14 years (211,744 person-years), 171 cases of CVD were identified. A significant inverse association was found between the MQI and CVD risk with multivariable-adjusted HR for the highest vs. the lowest quartile of 0.60 (95% IC, 0.38-0.96; P-trend = 0.024). Conclusion In this Mediterranean cohort, we found a significant inverse relationship between a multidimensional MQI (expressing high-quality macronutrient intake) and a lower risk of CVD.