Objective: To compare the 6-month angiographic and long-term (3-year) clinical outcomes of sirolimus-eluting stent (SES) implantation and intracoronary brachytherapy (ICBT) diffuse in-stent restenosis (ISR). Background: The safety and long-term effectiveness of SES implantation for diffuse ISR has not been ascertained. Methods: SES implantation for diffuse ISR was performed in 120 consecutive patients. Data from this group were compared to those from 240 patients treated with beta-radiation with ¹⁸⁸Re-MAG₃-filled balloon. The radiation dose was 15 or 18 Gy at a depth of 1.0 mm into the vessel wall. The primary end point was 3-year major adverse cardiac events (MACE) including myocardial infarction (MI), death, target lesion revascularization (TLR). The secondary end point was in-segment 6-month angiographic restenosis. Results: The two groups were similar in baseline clinical and angiographic characteristics. Mean lesion length was 25.1짹14.2 mm in SES group and 24.5.9짹10.4mm in ICBT group (p=0.15). In-stent acute gain was greater in SES group than ICBT group (2.23짹0.62 mm vs. 1.91짹0.54 mm, p<0.001). We obtained 6-month angiographic follow-up in 287 patients (79.7%). In-segment angiographic restenosis was 5.8% (7/94) in SES group and 26.4% (51/193) in ICBT group (p<0.05). Two MI (one each group) and three deaths (2 from SES group, 1 from ICBT group) occurred during 3-year follow-up. TLR (3.3% vs. 15.4%, p=0.002) and MACEs (5.0% vs. 16.3%, p=0.01) were lower in SES group than ICBT group during 3-year follow-up. Conclusions: SES implantation is more effective in reducing recurrent restenosis and improving long-term clinical outcomes than ICBT for diffuse ISR.