Objective: To assess the prospective association between ultra-processed food consumption and all-cause mortality and to examine the effect of theoretical iso-caloric non-processed foods substitution. Patients and Methods: A population-based cohort of 11,898 individuals (mean age 46.9 years, and 50.5% women) were selected from the ENRICA study, a representative sample of the noninstitutionalized Spanish population. Dietary information was collected by a validated computer-based dietary history and categorized according to their degree of processing using NOVA classification. Total mortality was obtained from the National Death Index. Follow-up lasted from baseline (20082010) to mortality date or December 31th, 2016, whichever was first. The association between quartiles of consumption of ultra-processed food and mortality was analyzed by Cox models adjusted for the main confounders. Restricted cubic-splines were used to assess dose-response relationships when using iso-caloric substitutions. Results: Average consumption of ultra-processed food was 385 g/d (24.4% of the total energy intake). After a mean follow-up of 7.7 years (93,599 person-years), 440 deaths occurred. The hazard ratio (and 95% CI) for mortality in the highest versus the lowest quartile of ultra-processed food consumption was 1.44 (95% CI, 1.01-2.07; P trend=.03) in percent of energy and 1.46 (95% CI, 1.04-2.05; P trend=.03) in grams per day per kilogram. Isocaloric substitution of ultra-processed food with unprocessed or minimally processed foods was associated with a significant nonlinear decrease in mortality. Conclusion: A higher consumption of ultra-processed food was associated with higher mortality in the general population. Furthermore, the theoretical iso-caloric substitution ultra-processed food by unprocessed or minimally processed foods would suppose a reduction of the mortality risk. If confirmed, these findings support the necessity of the development of new nutritional policies and guides at the national and international level. (C) 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.