Background and aimsSeveral studies reported an increased cancer risk related to lower-extremity peripheral artery disease (PAD) but had important caveats: not accounting for key confounders like smoking, follow-up <10 years, or no race-specific results. To assess the long-term independent association of PAD with cancer incidence in a bi-racial community-based cohort. MethodsWe categorized 13,106 ARIC participants without cancer at baseline (mean age 54.0 [SD 5.7] years, 45.7 % male, and 26.1 % Black) into symptomatic PAD (clinical history or intermittent claudication), asymptomatic PAD (ankle-brachial index [ABI] ≤0.9), and five ABI categories (0.1-interval between 0.9 and 1.3 and > 1.3). We used cancer registries and medical records to ascertain cancer cases and ran multivariable Cox models. ResultsDuring the median follow-up of 25.3 years, there were 4143 incident cancer cases. 25-year cumulative incidence was 37.2 % in symptomatic PAD, 32.3 % in asymptomatic PAD, and 28.0–31.0 % in the other categories. Symptomatic and asymptomatic PAD remained significantly associated with cancer incidence after adjusting for potential confounders, including smoking and diabetes (hazard ratio [HR] 1.42 [1.05–1.92] and 1.24 [1.05–1.46], respectively). When stratified by smoking status, we observed a robust association of PAD (symptomatic and asymptomatic combined) vs. no PAD with cancer risk in ever smokers (HR 1.42 [1.21–1.67]) but not in never smokers. The results were most evident for lung cancer (HR 2.16 (95 %CI 1.65–2.83) for PAD vs. no PAD within ever smokers). ConclusionsSymptomatic and asymptomatic PAD conferred cancer risk, particularly among ever smokers and for lung cancer. Patients with PAD should receive evidencebased cancer prevention and screening.