Purpose: To evaluate 6-month outcomes of drug-coated balloon (DCB) angioplasty of infrapopliteal lesions in patients with chronic limb-threatening ischemia (CLTI).Methods: We analyzed 6-month follow-up data from the 10-center PRIME-WIFI prospective registry on 300 consecutive patients (33.000% female) with CLTI who underwent DCB angioplasty for infrapopliteal arterial lesions. The primary outcome was freedom from major adverse event (MAE), a composite of major amputation, all-cause death, and clinically-driven target limb reintervention (CD-TLR). Secondary outcomes included amputation-free survival (AFS), freedom from each primary outcome component, primary sustained clinical improvement, and quality of life (QOL) score. Independent risk factors of MAE were determined using Cox proportional hazards regression analysis.Results: A total of 409 infrapopliteal lesions in 312 limbs were treated with DCB, with 54.167% of the limbs being treated for isolated infrapopliteal lesions. By Kaplan-Meier analysis, at 6 months post- procedure (follow-up rate, 85.000%), freedom from MAE was 86.353%; AFS was 90.318%; and freedom from major amputation, all-cause death, and CD-TLR were 96.429%, 93.480%, and 95.079%, respectively. At 6-month follow-up, 83.590% of patients showed primary sustained clinical improvement, and QOL score (4.902 +/- 1.388) improved compared with that before procedure (2.327 +/- 1.109; p<0.001). Chronic renal insufficiency, chronic obstructive pulmonary disease, Rutherford grade, and postoperative infrapopliteal runoff score were independent risk factors for MAE within 6 months.Conclusion: In CLTI, DCB angioplasty of infrapopliteal lesions yields acceptable early efficacy and safety.Clinical impact: This study evaluated the 6-month outcomes of DCB angioplasty in infrapopliteal lesions in CLTI patients by analyzing multicenter prospective data, showing that infrapopliteal DCB angioplasty can be performed with acceptable freedom from MAE rate, amputation-free survival rate, freedom from major amputation rate, survival rate, and freedom from CD-TLR rate. No patient experienced DCB-related intraoperative distal embolism. Chronic renal insufficiency, chronic obstructive pulmonary disease, Rutherford grade and postoperative infrapopliteal runoff score were independent risk factors for MAE within 6 months. Comparative real-world studies are needed.