Because late vessel failure has been speculated as a possible limitation of vascular brachytherapy, we conducted a prospective clinical evaluation at 6, 12, 24, and 36 months of follow-up after irradiation with strontium-90/yttrium-90 for in-stent restenosis, regardless of the patient's symptomatic status. We report complete 3-year follow-up data for 106 consecutive patients. The cumulative rate of death at 6, 12, 24, and 36 months was 0.9%, 0.9%, 0.9%, and 1.9% respectively. The corresponding rates for acute ST-elevation myocardial infarction were 2.8%, 4.7%, 4.7%, and 4.7%, respectively. The cumulative rate of late thrombotic occlusion at 6, 12, 24, and 36 months was 3.8%, 4.7%, 4.7%, and 4.7%, respectively. The corresponding rates of target lesion revascularization and target vessel revascularization were 8.5% and 12.3% (p = 0.046), 14.2% (p = 0.157) and 18.0% (p = 0.046), 12.3% and 18.9% (p = 0.008), and 21.7% (p = 0.083) and 29.2% (p = 0.005), respectively. The cumulative rate of all major adverse cardiovascular events at 6, 12, 24, and 36 months was 16.1%, 24.5% (p = 0.003), 27.4% (p = 0.083), and 35.8% (p = 0.003), respectively. In conclusion, these results indicate a delayed and, even in the third year after the index procedure, continued restenotic process after beta irradiation of in-stent restenotic lesions.