In a pivotal shift for peripheral arterial disease (PAD) management, healthcare experts are now integrating smoking-related DNA methylation profiling into clinical risk stratification. Recent findings underscore a direct correlation between DNA methylation at smoking-related loci and elevated mortality risk in PAD patients, prompting a unified approach that prioritizes this biomarker for more accurate risk assessments. Concurrently, prospective studies will be launched to validate and enhance methylation-based mortality predictions, setting the stage for personalized treatment strategies that could significantly improve patient outcomes.