<p>Drug-coated balloon (DCB) angioplasty is an effective endovascular therapy for femoropopliteal artery (FPA) disease in patients with peripheral artery disease (PAD). However, the long-term impact of statin and anticoagulant therapy on restenosis after DCB treatment remains unclear. This multicenter observational study analyzed data from 2507 PAD patients undergoing DCB angioplasty for symptomatic FPA disease in the POPCORN registry. Patients were classified into three groups based on medication status at the time of revascularization: No medication, One medication (statin or anticoagulant), and Two medications (both). Additional analyses were performed to separately evaluate statins, DOACs, and warfarin. Cox proportional hazards models with mixed effects assessed the association between medication use and restenosis risk in the short-term (&lt; 1&#xa0;year) and longer-term periods. In the short-term, neither one nor two medications significantly reduced restenosis risk. In contrast, during the longer-term period, One medication was associated with reduced restenosis (HR: 0.78, 95% CI: 0.64–0.95; P = 0.014), and Two medications showed further benefit (HR: 0.66, 95% CI: 0.46–0.95; P = 0.025). Based on additional analyses, both statin and DOAC use were independently associated with reduced restenosis risk, while warfarin showed no significant benefit. Statin and anticoagulant therapies did not reduce short-term restenosis but significantly lowered longer-term risks. These findings support the role of these medications in improving the durability of revascularization following DCB treatment for FPA disease. Particularly, additional analyses indicated that the benefit in the longer-term was primarily driven by statin and DOAC use.</p> Graphical abstract <p></p>