Previous studies have illustrated the potential superiority of drug-coated balloons (DCBs) in maintaining patency after initial angioplasty for arteriovenous fistula (AVF) dysfunction due to stenosis. Our trial evaluated the efficacy and safety of DCBs for preventing fistula restenosis in Chinese hemodialysis patients. Multicenter, prospective, randomized, open-label, blinded-endpoint, controlled trial. A total of 161 hemodialysis patients with fistula dysfunction from 10 centers in China. Subjects were randomized 1:1 to treatment with initial dilation following DCB or only plain high-pressure balloon (HPB) angioplasty. The primary endpoint was target lesion primary patency, defined as target lesion intervention-free survival in conjunction with an ultrasound-measured peak systolic velocity ratio (PSVR) ≤ 2.0 at six months. The secondary endpoints included (1) device, technical, clinical, and procedural success; (2) major adverse events; (3) degree of target lesion stenosis at 6 months; and (4) clinically driven target lesion and target shunt revascularization within 12 months. The percentage with target lesion primary patency as defined by a PSVR ≤ 2.0 was higher in the DCB group than in the control group (DCB 65% vs. control 37%, rate difference 28%, 95% CI 13%-43%, P<0.001) at 6 months. The target lesion and target shunt intervention-free survival of the DCB group were not superior to those of the control group at 6 months (P=0.3 and P= 0.2, respectively) but were superior at 12 months (target lesion, DCB 73% vs. control 58%, P=0.04; target shunt, DCB 73% vs. control 57%, P=0.04). Average degree of target lesion stenoses at 6 months was not significantly different between the two groups (DCB 44% ± 16% vs. control 49% ± 18%, P=0.09). There were no significant differences in major adverse events or in device, technical, clinical, or procedural success rates between the groups. Small sample size; short follow-up period; procedural differences between the two groups such as unequal inflation times, and balloon lengths. Compared to conventional HPB angioplasty, DCB treatment achieved superior primary patency defined using PSVR measured at 6 months and superior intervention-free survival of both the target lesion and the target shunt at 12 months without evidence for greater adverse events. Copyright © 2021. Published by Elsevier Inc.