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Objectives: To determine the one-year and five-year occurrence and prognosticators of major adverse cardiac events (MACE: composition of all-cause death, myocardial infarction, target vessel revascularization, and vessel thrombosis), mortality, and target lesion revascularization (TLR) in patients with in-stent restenosis (ISR) treated with drug-eluting balloons (DEBs)., Background: DEBs have become an emerging therapeutic option for ISR. We report the results of a single-center retrospective study on the treatment of ISR with DEB., Methods: 94 consecutive patients with ISR treated with the paclitaxel-eluting balloon were retrospectively studied between August 2011 and December 2019., Results: The one-year MACE rate was 11.8%, and the five-year MACE rate was 39.8%. The one-year mortality was 5.3%, and the five-year mortality rate was 21.5%. The one-year TLR rate was 4.3%, and the five-year rate was 18.7%. The univariable-Cox proportional hazard models for TLR showed lesion length, and the number of DEBs per vessel is associated with adverse outcomes with H.R. of 1.038 (1.007-1.069) and 4.7 (1.6-13.8), respectively., Conclusion: Our data indicate that at one year, DEBs provide an effective alternative to stenting for in-stent restenosis. Our five-year data, representing one of the longest-term follow-ups of DEB use, demonstrate high rates of MACE. The high five-year MACE reflects all-cause mortality in a high-risk population. This is offset by a reasonable five-year rate of TLR, indicating that DEB provides both short-term and long-term benefits in ISR., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Kyle Murnaghan et al.)