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Purpose To compare lesion primary patency and restenosis rates between drug-eluting balloon (DEB) percutaneous transluminal angioplasty (PTA) and conventional balloon PTA (cPTA) in the treatment of arteriovenous fistula (AVF) and arteriovenous graft (AVG) stenosis. Materials and Methods In this prospective study, 119 participants (mean age, 59.2 years; 79 men, 40 women) with failing AVFs (n = 98) or AVGs (n = 21) were randomly assigned to undergo either DEB PTA (n = 59) or cPTA (n = 60) from January 2012 to May 2013. Primary end points were lesion primary patency and restenosis rates at 6 months; secondary outcomes were anatomic and clinical success after PTA, circuit primary patency at 6 months and 1 year, and lesion primary patency at 1 year. Statistical analysis was performed by using the Kaplan-Meier product limit estimator, and hazard ratio was calculated by using Cox proportional hazards regression. Complication rates were assessed in both groups. Results Estimated lesion primary patency in the DEB PTA and cPTA arms was 0.81 and 0.61, respectively, at 6 months (P = .03) and 0.51 and 0.34, respectively, at 1 year (P = .04). Estimated circuit primary patency in the DEB PTA and cPTA arms was 0.76 and 0.56, respectively, at 6 months (P = .048) and 0.45 and 0.32, respectively, at 1 year (P = .16). Restenosis rate was 34.0% (16 of 47) for DEB PTA and 62.9% (22 of 35) for cPTA at 6 months (P = .01). No major complications were noted. Conclusion Drug-eluting balloon angioplasty was effective in prolonging lesion primary patency of dialysis access stenoses at 6 months and 1 year. © RSNA, 2018.