In this cohort study involving 9399 current and former smokers from the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease study, we assessed the relationship between artificial intelligence-quantified mucus plugs on chest CTs and all-cause mortality. Our results revealed a significant positive association, particularly for those with COPD GOLD stages 1-4, with HRs of 1.18 for 1-2 mucus-obstructed bronchial segments and 1.27 for ≥3 obstructed segments. This corroborates previous visual mucus plug counting research and demonstrates the relevance of mucus plugs in COPD pathology and as a marker for risk assessment. Automated mucus plug quantification methods may provide an efficient tool for both clinical evaluations and research.