BACKGROUND AND OBJECTIVES: A cutting balloon angioplasty for the treatment of diffuse in-stent restenosis has been reported to be superior to conventional percutaneous transluminal coronary angioplasty. Intracoronary radiation therapy is also a novel technique for preventing a recurrence of in-stent restenosis following percutaneous coronary intervention. Holmium (166Ho) is a high-energy beta-emitter, which is available in liquid form. We performed a cutting balloon angioplasty, with subsequent intracoronary 166Ho brachytherapy, for the treatment of in-stent restenosis. SUBJECTS AND METHODS: Fifty two patients, with in-stent restenosis, were treated with cutting balloon angioplasy and intracoronary 166Ho brachytherapy. For the irradiation, a balloon approximately 10 mm longer than the stent was used. Radiation doses of 18 Gy at a depth of 1 mm from balloon-artery interface were used. A quantitative coronary angiography was performed during the procedure and at the 6-month follow-up. The patients were followed clinically for an average of 16.8+/-9.8 months. RESULTS: The procedures were successful in all patients. The minimal luminal diameter of in-stent restenosis lesions, initially and after treatment, and the lesion length were 0.58+/-0.30 and 2.55+/-0.29 mm, and 20.7+/-7.1 mm, respectively. Thirty four (65.4%) patients completed the angiographic follow-up at 6 months. The minimal luminal diameter of lesion and late loss were 2.03+/-0.83 and 0.57+/-0.79 mm, respectively. The target lesion restenosis rate was 14.7%. No patients presented with MACE, such as MI, death or stent thrombosis. CONCLUSION: The combination of cutting balloon angioplasty and intracoronary 166Ho brachytherapy was feasible, safe and effective for the treatment of diffuse in-stent restenosis.