To prospectively evaluate the association between modifiable lifestyle factors and peripheral artery disease (PAD) among individuals with type 2 diabetes (T2D).We included 14,543 individuals with T2D from the UK Biobank. We defined a weighted healthy lifestyle score using nonsmoking, regular physical activity, high-quality diet, moderate alcohol consumption, optimal waist-to-hip ratio, and adequate sleep duration, and categorized into unfavorable, intermediate, and favorable lifestyles. We created a genetic risk score (GRS) using 19 single nucleotide polymorphisms previously found to be associated with PAD. We modeled the association between lifestyle score and PAD, overall and stratified by PAD genetic susceptibility.After a median 13.5 years of follow-up, 628 incident cases of PAD were documented. A linear inverse association between the weighted lifestyle score and PAD was observed, with a hazard ratio (HR) (95% CI) of 0.27 (0.19, 0.38) for favorable compared with unfavorable lifestyle (Ptrend < 0.0001). An estimated 58.3% (45.0%, 69.1%) of PAD in this population could be potentially avoidable if all participants attained a favorable lifestyle. Moreover, the PAD GRS was associated with increased PAD risk (HR [95% CI] per SD increment: 1.13 [1.03, 1.23]). A favorable lifestyle was able to partially mitigate the excess risk of PAD associated with higher GRS, albeit as a nonsignificant interaction. Several biomarkers in the lipid metabolism, hepatic/renal function, and systemic inflammation pathways collectively explained 13.3% (8.5%, 20.1%) of the association between weighted lifestyle score and PAD.A favorable lifestyle was associated with lower risk of PAD among individuals with T2D, independent of genetic predisposition to PAD.© 2024 by the American Diabetes Association.