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). Conclusions: Higher frequency of ultra-processed food intake was associated with higher risk of all-cause mortality in a representative sample of US adults. More Longitudinalstudies with dietary data reflecting the modern food supply are needed to confirm our results.