Background: The Global Limb Anatomic Staging System (GLASS) was proposed to assess the procedural complexity and technical failure rate and stratify the anatomic pattern of chronic limb-threatening ischemia (CLTI). However, more evidence is needed to validate the GLASS in staging outcomes after endovascular therapy in patients with CLTI treated with drug-coated balloons (DCBs). This study aims to evaluate the role of the GLASS in predicting outcomes of CLTI patients treated with DCBs.Methods: This multicenter, retrospective cohort study enrolled patients with CLTI treated with DCBs from July 2016 to June 2019. GLASS stages were assigned for every limb. The limb-based patency (LBP) rate, clinically driven target lesion revascularization (CD-TLR) rate, clinical improvement, and safety endpoints were analyzed and compared across the GLASS stages over 12 months of follow-up. Risk factors for the loss of LBP were identified using Cox regression analysis.Results: A total of 90 limbs were enrolled, with 55 (61.1%) having isolated femoropopliteal lesions and 35 (38.9%) having femoropopliteal and infrapopliteal lesions. Of the limbs, 17 (18.9%), 12 (13.3%), and 61 (67.8%) were assigned to GLASS stages I, II, and III, respectively. The Kaplan-Meier estimate of the 12-month LBP was 65.4%, and no difference was found among the different stages (stage I 81.1%; stage II 85.2%; stage III 54.4%; P=0.080). The LBP was lower in stage III than in stages I and II combined (stage I and II 83.5%; stage III 54.4%; P=0.027). Similar results were found for the freedom from CD-TLR rates among the different stages. The ankle-brachial index values improved from 0.42 +/- 0.29 to 0.78 +/- 0.35 at follow-up (P<0.001). The rates of mortality, any amputation, and major amputation were similar among the groups. GLASS stage III and coronary heart disease were identified as independent risk factors for the loss of LBP at 12 months.Conclusions: The 1-year LBP and freedom from CD-TLR rates were lower in GLASS stage III than in stages I and II. The GLASS classification could predict the outcomes of CLTI patients with femoropopliteal lesions treated with DCB.