No previous study has assessed the relationship between overall macronutrient quality and all-cause mortality. We aimed to prospectively examine the association between a multidimensional macronutrient quality index (MQI) and all-cause mortality in the SUN (Seguimiento Universidad de Navarra) (University of Navarra Follow-Up) study, a Mediterranean cohort of middle-aged adults. Dietary intake information was obtained from a validated 136-item semi-quantitative food-frequency questionnaire. We calculated the MQI (categorized in quartiles) based on three quality indexes: the carbohydrate quality index (CQI), the fat quality index (FQI), and the healthy plate protein source quality index (HPPQI). Among 19,083 participants (mean age 38.4, 59.9% female), 440 deaths from all causes were observed during a median follow-up of 12.2 years (IQR, 8.3-14.9). No significant association was found between the MQI and mortality risk with multivariable-adjusted hazard ratio (HR) for the highest vs. the lowest quartile of 0.79 (95% CI, 0.59-1.06; P-trend = 0.199). The CQI was the only component of the MQI associated with mortality showing a significant inverse relationship, with HR between extreme quartiles of 0.64 (95% CI, 0.45-0.90; P-trend = 0.021). In this Mediterranean cohort, a new and multidimensional MQI defined a priori was not associated with all-cause mortality. Among its three sub-indexes, only the CQI showed a significant inverse relationship with the risk of all-cause mortality.