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Coronary artery disease (CAD) is the leading cause of death for both men and women in the United States. Percutaneous coronary intervention (PCI) with drug eluting stents (DES) has been a major advance in treatment with over 600,000 stents deployed annually. In-stent restenosis occurs in up to 10% of patients and is often managed with repeat DES placement. However, when stent-in-stent restenosis (SISR) occurs, options remain limited, and one technique includes angioplasty followed by intravascular brachytherapy (IVBT). We undertook this study to review efficacy and safety of PCI followed by IVBT for patients experiencing SISR. We retrospectively reviewed 78 patients from 2016-2021 with SISR involving 91 vessels who received PCI with balloon angioplasty followed by IVBT. IVBT with a strontium-90 source was delivered via The Beta Cath® system (Novoste; Bes Vascular, Norcross, Ga, USA). The radiation dose delivered was 23Gy to vessels of ≥ 3.5mm in diameter, while 18.4 Gy was delivered to vessels of < 3.5 mm diameter. Radiation was prescribed to an area encompassing the angioplasty injury length with a 10mm longitudinal margin on each side. Major adverse cardiac events (MACE) include myocardial infarction (MI), stroke and all-cause death. Target vessel revascularization (TVR) was defined as percutaneous or surgical revascularization of the previously treated vessel. Median age was 67 years. All patients had at least 2 drug-eluting stents previously placed in the affected vessel. Sixty-one treatments were delivered to the left anterior descending artery or the right coronary artery with the remaining 30 delivered to either to a circumflex vessel or marginal artery. Sixty-three percent received 23Gy while 37% received 18.4Gy. One patient experienced cardiac arrest while receiving intervention, but no other procedure-related toxicities were reported. Median follow up was 22.8 months (range 0.9-60.6). All patients were symptomatic prior to IVBT and 44% experienced symptomatic reduction after treatment. The most common persistent symptom was angina in 71% of those patients. MACE after IVBT include MI in 18%, stroke in 5% and all-cause death occurring in 16% at a median time of 9.3 months after treatment (range 0.9-29.6). Seventy-seven percent had patency of the irradiated lesion, while 23% percent experienced restenosis requiring TVR. PCI followed by IVBT is a safe and effective paradigm for patients with high-risk coronary artery disease experiencing SISR, who have few other treatment options. [ABSTRACT FROM AUTHOR]