We previously showed non-inferiority of a low-dose paclitaxel-coated balloon (PCB) with citrate excipient (Agent PCB) as compared to normal-dose iopromide excipient (SeQuent Please PCB) in terms of angiographic and clinical endpoints at 12 months. The long-term clinical efficacy and safety of Agent PCB is not defined. 262 patients (323 DES-ISR lesions) were enrolled in this study and treated with either Agent PCB (125 patients, 151 lesions) in the ISAR-DESIRE 3a trial or with SeQuent Please PCB (137 patients, 172 lesions) in the setting of the randomized ISAR-DESIRE 3 trial with similar in- and exclusion criteria serving as historical control arm. The follow-up period was extended to 7 years. The efficacy and safety endpoints of this analysis were target-lesion revascularization (TLR), death, myocardial infarction (MI) and target lesion thrombosis (TLT) at 7 years. At 7 years, 206 patients (78.6%) were alive. The risks of TLR (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 0.87-1.90; p = 0.205), death (HR: 1.38, 95% CI: 0.82-2.35; p = 0.227), MI (HR: 1.10, 95% CI: 0.39-3.15; p = 0.852) and TLT (HR: 2.18, 95% CI: 0.20-24.10; p = 0.523) were comparable between Agent PCB and SeQuent PCB. Multivariate analysis showed comparable risks of TLR, death and MI between both PCB devices. In patients treated for DES-ISR by angioplasty with Agent PCB and SeQuent Please PCB, there was no statistically significant difference in TLR at 7 years. Randomized trials with standardized lesion preparation and long-term follow-up are warranted to further evaluate comparative efficacy of both devices. (ClinicalTrials. gov Identifier: NCT02367495).