Purpose <p>To compare the efficacy and safety of predilation-free angioplasty with a scoring paclitaxel-coated balloon catheter versus conventional plain balloon angioplasty for failing arteriovenous access.</p> Materials and Methods <p>This prospective multicenter randomized controlled trial enrolled adults with malfunctioning mature arteriovenous fistulas or grafts at nine centers in China between August 21, 2019, and January 4, 2021. Participants were randomly assigned in a 1:1 ratio to predilation-free scoring paclitaxel-coated balloon angioplasty or conventional plain balloon angioplasty. The primary endpoint was 6-month target lesion primary patency. Secondary endpoints included device success, procedural success, clinical success, residual stenosis, 12-month target lesion primary patency, and safety.</p> Results <p>A total of 219 treated participants were analyzed, including 109 in the scoring paclitaxel-coated balloon group and 110 in the control group. Six-month target lesion primary patency was 78.9% versus 57.3% (center-adjusted absolute difference, 21.2 percentage points; 95% CI 8.1–37.1 percentage points; <i>P</i> = 0.004). Twelve-month target lesion primary patency was 63.5% (66/104) versus 52.4% (55/105) (absolute difference, 11.1 percentage points; 95% CI − 2.2 to 24.4 percentage points; <i>P</i> = 0.1043). Device success, procedural success, clinical success, mortality, adverse events, and serious adverse events did not differ between groups. Acute gain was greater, and residual stenosis was lower with the scoring paclitaxel-coated balloon.</p> Conclusion <p>Predilation-free angioplasty with a scoring paclitaxel-coated balloon improved a 6-month target lesion primary patency without increasing adverse events in patients with failing arteriovenous access.</p> <p><i>Level of Evidence</i>: Level 1, randomized controlled trial.</p> Graphical Abstract <p></p>