At present, vascular brachytherapy is the only efficient therapy for in-stent restenosis. Nevertheless, edge restenosis often related to geographical miss has been identified as a major limitation of the technique. The non-slippery cutting balloon has the potential to limit vascular barotraumas, which, together with low-dose irradiation at both ends of the radioactive source, are the prerequisite for geographical miss. This prospective study aimed to examine the efficacy of combining cutting balloon angioplasty and brachytherapy for in-stent restenosis. The Radiation in Europe NOvoste (RENO) registry prospectively tracked all patients who had been treated by coronary beta-radiation with the Beta-Cath System (Novoste Corporation, Brussels, Belgium) but were not included in a randomized radiation trial. A subgroup of patients with in-stent restenosis treated by cutting balloon angioplasty and coronary beta-radiation (group 1, n = 166) was prospectively defined, and clinical outcomes of patients at 6 months were compared with those of patients treated by conventional angioplasty and coronary beta-radiation (group 2, n = 712). At 6-month follow-up, there was a significant difference between groups 1 and 2 in target vessel revascularization (10.2% versus 16.6% respectively; p = 0.04) and in the incidence of major adverse clinical events (MACE) including death, myocardial infarction, and revascularization (10.8% versus 19.2%; p = 0.01). This observation was confirmed by a multivariate analysis indicating a lower risk for MACE at 6 months (odds ratio: 0.49; confidence intervals: 0.27 0.88; p = 0.02). Compared to conventional angioplasty, cutting balloon angioplasty prior to coronary beta-radiation with the Beta-Cath System seems to improve the 6-month clinical outcome in patients with in-stent restenosis.