no previous large prospective studies have assessed the global quality of macronutrients in association with the risk of overweight/obesity. to prospectively assess the association of an overall macronutrient quality index (MQI) with weight change and the incidence of overweight/obesity in the Seguimiento Universidad de Navarra (SUN) cohort. the diet of 9,344 Spanish university graduates (mean age: 36.5 [SD, 11.1]) was assessed through a validated 136-item food frequency questionnaire. The MQI was calculated as the sum of the Carbohydrate Quality Index, the Fat Quality Index, and the Healthy Plate Protein Quality Index. Participants were classified into groups according to MQI. Incident overweight/obesity was defined if follow-up questionnaires indicated BMI was ≥ 25 kg/m2. Multiple linear regression models and Cox proportional hazard models were used to assess the average yearly weight change and the risk of overweight/obesity over follow-up time. 2,465 cases of incident overweight/obesity were identified (median follow-up: 10.7 years). Increasing MQI was significantly associated with lower annual weight gain (g): ß coefficient: -99.0, (95 % CI: -173.6 to -24.5) in the Q4 vs Q1, p for trend = 0.007. In the fully adjusted model the incidences of overweight/obesity in Q4 and Q1 were 21.7 % (431 cases) and 29.3 % (954 cases), respectively. The adjusted HR was 0.87 (95 % CI, 0.77-0.98, p for trend = 0.036). When we used repeated analyses updating the MQI after 10 years of follow-up, results remained similar. a significant inverse association between a multidimensional MQI and the risk of overweight/obesity was found in this Mediterranean cohort of adults.