To evaluate the association between ultra-processed food intake and all-cause mortality and CVD mortality in a nationally representative sample of US adults. Prospective analyses of reported frequency of ultra-processed food intake in 1988-1994 and all-cause mortality and CVD mortality through 2011. The Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994).ParticipantsAdults aged ≥20 years (n 11898). Over a median follow-up of 19 years, individuals in the highest quartile of frequency of ultra-processed food intake (e.g. sugar-sweetened or artificially sweetened beverages, sweetened milk, sausage or other reconstructed meats, sweetened cereals, confectionery, desserts) had a 31% higher risk of all-cause mortality, after adjusting for demographic and socio-economic confounders and health behaviours (adjusted hazard ratio=1·31; 95% CI 1·09, 1·58; P-trend = 0·001). No association with CVD mortality was observed (P-trend=0·86). Higher frequency of ultra-processed food intake was associated with higher risk of all-cause mortality in a representative sample of US adults. More longitudinal studies with dietary data reflecting the modern food supply are needed to confirm our results.