Intravascular radiation (IR) is emerging as a potential solution for the prevention and treatment of restenosis. Subacute thrombosis late coronary occlusion of the target lesion after intracoronary brachytherapy has been described in two studies. None of these studies assessed in detail the evolution of side branches following IR. The purpose of this study was to determine the frequency of side-branch occlusion in patients undergoing IR. We evaluated the procedural and 6-month follow-up angiograms of 170 consecutive patients enrolled in the GAMMA-I and WRIST studies who presented a major side branch (diameter > 1.5 mm) at the treated lesion. Major side branches treated during the procedure and/or total occlusion of the main branch were excluded for analysis. Sixty-three patients (control = 30, irradiated = 33) were identified and side branches were classified in one of three categories: no significant stenosis, > 50% stenosis, and occluded. The baseline patient and lesion characteristics were similar among the classified groups. No difference was observed between the control and irradiated arteries after the procedure for side-branch occlusion (14% and 9%, P = NS). A significant decrease of restenosis was observed after IR compared to control (20% vs. 70%: P < 0.001). The patency rates and rates of side-branch occlusion were similar between the two groups. However, in the control group, 50% of the side-branch occlusions that occurred after the procedure were patent at 6-month follow-up. In contrast, in the irradiated group, the incidence of side-branch occlusion increased from 9% to 15% at 6-month follow-up in the irradiated group. Low doses of radiation applied to noninjured side branches are not associated with adverse effects. The absence of restoration patency followed by IR is most likely a consequence of a delayed healing process.