Higher ultra-processed food intake has been linked with several cardiometabolic and cardiovascular diseases. However, prospective evidence from US populations remains scarce. To test the hypothesis that higher intake of ultra-processed foods is associated with higher risk of coronary artery disease. A total of 13,548 adults aged 45–65 y from the Atherosclerosis Risk in Communities study were included in the analytic sample. Dietary intake data were collected through a 66-item FFQ. Ultra-processed foods were defined using the NOVA classification, and the level of intake (servings/d) was calculated for each participant and divided into quartiles. We used Cox proportional hazards models and restricted cubic splines to assess the association between quartiles of ultra-processed food intake and incident coronary artery disease. There were 2006 incident coronary artery disease cases documented over a median follow-up of 27 y. Incidence rates were higher in the highest quartile of ultra-processed food intake (70.8 per 10,000 person-y; 95% CI: 65.1, 77.1) compared with the lowest quartile (59.3 per 10,000 person-y; 95% CI: 54.1, 65.0). Participants in the highest compared with lowest quartile of ultra-processed food intake had a 19% higher risk of coronary artery disease (HR: 1.19; 95% CI: 1.05, 1.35) after adjusting for sociodemographic factors and health behaviors. An approximately linear relation was observed between ultra-processed food intake and risk of coronary artery disease. Higher ultra-processed food intake was associated with a higher risk of coronary artery disease among middle-aged US adults. Further prospective studies are needed to confirm these findings and to investigate the mechanisms by which ultra-processed foods may affect health.