Background In-stent restenosis presents a major limitation of intracoronary stenting. Ionizing radiation has been shown to reduce the recurrence of restenosis after stent placement. We are reporting the effects of intracoronary radiation therapy versus placebo for the clinical and angiographic outcomes of patients with diffuse in-stent restenosis. Methods A total of 332 patients with in-stent restenosis underwent successful coronary intervention, then were blindly randomized to receive either intracoronary beta radiation using a 32P source (RT) or a sham placebo treatment (C) delivered into a centering balloon catheter via an automatic afterloader. Longer lesions (> 22 mm of dilated length) were treated with tandem positioning of the study wire. The primary safety endpoint was the composite occurrence of major adverse cardiac events (MACE) defined as death, myocardial infarction (MI), and repeat target lesion revascularization (TLR) at nine months. The primary efficacy endpoint was binary angiographic restenosis rate in the analysis segment during the nine-month follow-up. The secondary endpoints were MACE with target vessel revascularization (TVR) and angiographic endpoints of restenosis and the magnitude of late lumen loss indices. Findings Procedural success, in-hospital and 30 days complications were similar among the groups. For the primary safety endpoint, freedom from death, myocardial infarction, and repeat target lesion revascularization through 290 days was better in the radiated group (86 % RT vs. 69 % C, p = 0.0006). The binary angiographic restenosis rate was lower in the radiated group for the entire analyzed segment (26 % RT vs. 52 % C, p < 0.0001) – radiation also reduced the target lesion revascularization in long lesions (14 % RT vs. 37 % C, p = 0.005). Interpretation Vascular brachytherapy using pure-emitter 32P delivered into a centering catheter via an automatic afterloader reduced the overall revascularization in patients undergoing treatment for diffuse in-stent restenosis.