BACKGROUND: Intake of ultraprocessed foods (UPF) provides more than half of the daily energy US adults consume. Still, the prospective association of UPF consumption with mortality in the general US population remains understudied. OBJECTIVE: To investigate the prospective association of UPF consumption with mortality in a nationally representative sample of US adults. DESIGN: A prospective cohort analysis was conducted by linking baseline measurement from the National Health and Nutrition Examination Survey with mortality information from the National Death Index. The percentage of total energy consumed from UPF, defined by the Nova classification system, was computed based on dietary data collected using 24-hour diet recalls. PARTICIPANTS/SETTING: This study included 38 148 nationally representative US adults aged 20 years and older who participated in National Health and Nutrition Examination Survey between 2003-2004 and 2017-2018 and provided dietary intake data, with linkage to mortality data. MAIN OUTCOME MEASURES: Information on all-cause and cause-specific mortality was obtained from linkage to the National Death Index through December 31, 2019. STATISTICAL ANALYSIS PERFORMED: Cox proportional hazard models estimated the multivariable-adjusted hazard ratios and 95% CIs for the association between UPF intake and mortality. RESULTS: During a median follow-up of 8.0 years, 4611 deaths were confirmed, including 2064 deaths from cardiometabolic disorders and 1046 deaths from cancer. After multivariable adjustments, each 10-point increment in usual percentage of total energy from UPF was associated with a 9% higher risk of all-cause mortality (hazard ratio 1.09, 95% CI 1.04 to 1.14). The association remained significant after adjusting for the overall diet quality measured by the Health Eating Index 2015 (hazard ratio 1.06, 95% CI 1.00 to 1.11; P < .05). Among subgroups, sugar-sweetened beverages, ready-to-eat or -heat mixed dishes, ultraprocessed dairy products, and ultraprocessed oil/fat, condiments, and sauces were associated with an increased risk of all-cause or cause-specific mortality. Ultraprocessed vegetables and legumes were associated with a reduced risk. CONCLUSIONS: In this nationally representative study of US adults, higher consumption of UPF was associated with a higher risk of all-cause mortality, and this association was not fully explained by overall diet quality.