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Aims Drug-coated balloons (DCBs) are commonly used to treat in-stent restenosis (ISR) and selected de novo coronary lesions. However, long-term data from UK district general hospitals (DGH) are limited. This study evaluated the safety, efficacy, and long-term outcomes of DCB therapy for ISR and de novo coronary lesions at Royal Blackburn Hospital, a large DGH, and compared outcomes between different lesion types.Methods and Results Methods: We conducted a retrospective study at Royal Blackburn Hospital, involving 117 patients who underwent drug-coated balloon (DCB) therapy during percutaneous coronary intervention (PCI) between 2019 and 2022. Lesions were classified as in-stent restenosis (ISR; forty-one patients), de novo (73 patients), or stent thrombosis (3 patients; excluded from analysis). Clinical presentations included acute coronary syndrome (76 patients) and stable angina (41 patients). Left ventricular ejection fraction was normal in sixty-four patients, mildly impaired in twenty-two, moderately impaired in fifteen, and severely impaired in eleven patients. Procedural strategies included NC balloons were used in all cases, scoring balloons and intravascular ultrasound (IVUS), were primarily in ISR cases (scoring balloons: fifteen vs. four; IVUS: sixteen vs. 4). Paclitaxel-based DCBs were used in seventy-one patients, followed by sirolimus-based balloons. Small vessels (<2.75 mm) were treated more often in de novo lesions (47 vs. 7), while larger vessels (>3.0 mm) were predominant in ISR (34 vs. 26) which were statistically significant. Primary endpoints were target lesion revascularization (TLR) and all-cause mortality at 1 and 3 years, with secondary endpoints including target vessel failure (TVF) including MI, Heart failure hospitalization, stroke and non-target vessel revascularization.Results A study involving 114 patients showed that drug-coated balloons (DCB) yielded excellent outcomes for both in-stent restenosis (ISR) and de novo lesions. Cross-over stenting in de novo lesions was limited to two cases. At one-year, all-cause mortality was 0% for ISR and 6.8% for de novo lesions, with rates of 4.9% and 6.8%, respectively, at three years. Target vessel revascularization occurred in three ISR patients and two de novo patients after 1 year, but there were no events at 3 years. ISR primarily involved the left anterior descending artery (LAD; n=19), the right coronary artery (RCA; n=10), and multivessel ISR (n=3). De novo lesions included the left circumflex (LCX, n=15) and other branches. Scoring balloon and intravascular ultrasound (IVUS) were more often used in ISR cases. Paclitaxel-based balloons were used in 71 cases, particularly for small vessels (<2.75 mm) in de novo lesions (47 vs. 7), while ISR predominantly involved larger vessels (>3.0 mm). No significant differences in outcomes at 1 or 3 years were seen between the groups.Conclusions In this real-world experience from a large UK district general hospital, drug-coated balloon therapy for ISR and selected de novo coronary lesions showed excellent 1- and 3-year outcomes, with no significant between-group difference. These findings, which are effective in small-vessel disease and avoid added stent implantation, support broader adoption of DCB beyond tertiary centres.