Intracoronary gamma radiation is effective in reducing recurrent in-stent restenosis (ISR) involving native coronary arteries. This study compares the effectiveness and safety of intracoronary gamma radiation for the treatment of ISR in saphenous vein grafts (SVGs) versus native coronary arteries. In the Washington Radiation for In-Stent restenosis Trial (WRIST) series of gamma radiation trials, 1,142 patients with ISR (230 in SVG and 912 in native coronary arteries) completed 6-month clinical follow-up. All patients underwent balloon angioplasty, atherectomy, and/or restenting. Different ribbon lengths containing 6 to 23 seeds of iridium-192 were used to cover lesion lengths <80 mm. The prescribed radiation doses were 14 or 15 Gy at 2-mm radial distance from the center of the source. Baseline demographics showed that patients with SVGs were older (65 +/- 13 vs 61 +/- 11 years, p <0.001), more likely male (79% vs 64%, p <0.001), had more multivessel coronary disease (81% vs 50%, p <0.001), and less diffuse lesions (17 +/- 10 vs 24 +/- 12 mm, p <0.001). At 6 months, event-free survival was similar for patients with SVG ISR and native coronary ISR (82% vs 84%, p = 0.35). The SVG ISR population had a low rate of late total occlusion (4.6%) and late thrombosis (3.5%). Thus, treatment of ISR with gamma radiation in SVGs had similar outcome to native coronary arteries. The use of gamma radiation for the treatment of ISR should expand to SVGs.