Objective: To determine the association between ultra-processed food (UPF) intake and all-cause mortality in a representative sample of Spanish population. Design: Prospective cohort design in which follow-up lasted from baseline (1991) to mortality date or 31 December 2017, whichever was first. Dietary information was collected using a validated frequency questionnaire and categorised following the NOVA classification according to the extent of food processing. The association between consumption of UPF and mortality was analysed using Cox models. Isoenergetic substitution models were constructed to compare the health effects of the NOVA groups. Setting: Cohort from the Diet and Risk of Cardiovascular Diseases (CVD) in Spain (DRECE) study, representative of the Spanish population Participants: Totally, 4679 subjects between 5 and 59 years old. Results: Average consumption of UPF was 370 center dot 8 g/d (24 center dot 4 % of energy intake). After a median follow-up of 27 years, 450 deaths occurred. Those who consumed the highest amount of UPF had higher risk of mortality. For every 10 % of the energy intake from UPF consumption, an increase of 15 % in the hazard of all-cause mortality was observed (HR 1 center dot 15; (95 % CI 1 center dot 03, 1 center dot 27); P-value = 0 center dot 012). Substitution of UPF with minimally processed foods was significantly associated with a decreased risk of mortality. Conclusions: An increase in UPF consumption was associated with higher risk of all-cause mortality in a representative sample of the Spanish population. Moreover, the theoretical substitution of UPF with unprocessed or minimally processed foods leads to a decrease in mortality. These results support the need to promote diets based on unprocessed or minimally processed foods.