Context: Restenosis within bare-metal stents is often treated with repeat percutaneous coronary intervention, although subsequent recurrence rates are high, with vascular brachytherapy(VBT) affording the best results. The effectiveness of drug-eluting stents in this setting has not been established. Objective: To investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in patients with restenotic lesions after prior stent implantation in native coronary arteries. Design, Setting, and Patients: Prospective, multicenter, randomized trial conducted between June 6, 2003, and July 16, 2004, at 37 North American academic and community-based institutions in 396 patients with in-stent restenosis of a previously implanted bare-metal coronary stent(vessel diameter, 2.5-3.75 mm; lesion length, ≤ 46 mm). Interventions: Patients were randomly assigned to undergo angioplasty followed by VBT with a β source(n=201) or paclitaxel-eluting stent implantation(n=195). Clinical and angiographic follow-up at 9 months was scheduled in all patients. Main Outcome Measure: Ischemia-driven target vessel revascularization at 9 months. Results: Diabetes mellitus was present in 139 patients(35.1% ). Median reference vessel diameter was 2.65 mm and median lesion length was 15.3 mm. In the VBT group, new stents were implanted in 22 patients(10.9% )and in the paclitaxel-eluting stent group, multiple stents were required in 57 patients(29.2% ), with median stent length of 24 mm. Follow-up at 9 months was complete in 194 patients in the VBT group and 191 patients in the paclitaxel-eluting stent group(96.5% and 97.9% , respectively). For VBT and paclitaxel-eluting stents, respectively, the number of events and 9-month rates for ischemic target lesion revascularization were 27(13.9% ) vs 12(6.3% )(relative risk [RR], 0.45; 95% confidence interval [CI], 0.24-0.86; P=.01); for ischemic target vessel revascularization, 34(17.5% ) vs 20(10.5% )(RR, 0.60; 95% CI, 0.36-1.00; P=.046); and for overall major adverse cardiac events, 39(20.1% ) vs 22(11.5% )(RR, 0.57; 95% CI, 0.35-0.93; P=.02), with similar rates of cardiac death or myocardial infarction(10 [5.2% ] vs 7 [3.7% ]; RR, 0.71; 95% CI, 0.28-1.83; P=.48) and target vessel thrombosis(5 [2.6% ] vs 3 [1.6% ]; RR, 0.61; 95% CI, 0.15-2.50; P=.72). Angiographic restenosis at 9 months was 31.2% (53 of 170 patients) with VBT and 14.5% (25 of 172 patients) with paclitaxel-eluting stents(RR, 0.47; 95% CI, 0.30-0.71; P< .001). Conclusion: Treatment of bare-metal in-stent restenotic lesions with paclitaxel-eluting stents rather than angioplasty followed by VBT reduces clinical and angiographic restenosis at 9 months and improves event-free survival. Trial Registration: ClinicalTrials. gov Identifier: NCT00287573. Context: Restenosis within bare-metal stents is often treated with repeat percutaneous coronary intervention, although the recurrence rates are high, with vascular brachytherapy (VBT) affording the best results. The effectiveness of drug-eluting stents in this setting has not been established. Objective: To investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in patients with restenotic lesions after prior stent implantation in native coronary arteries. Design, Setting, and Patients: Prospective, multicenter, randomized trial conducted between June 6, 2003, and July 16, 2004, at 37 North American academic and community-based institutions in 396 patients with in-stent restenosis of a previously implanted bare-metal coronary stent (vessel diameter, 2.5-3.75 mm; lesion length, ≤ 46 mm) Interventions: Patients were randomly assigned to undergo angioplasty followed by VBT with a β source (n = 201) or paclitaxel-eluting stent implantation (n = 19 5). Clinical and angiographic follow-up at 9 months was scheduled in all patients. Main Outcome Measure: Ischemia-driven target vessel revascularization at 9 months. Results: Diabetes mellitus was present in 139 patients (35.1%). Median reference vessel diameter was 2.65 mm and median lesion length was 15.3 mm. In the VBT group, new stents were implanted in 22 patients (10.9%) and in the paclitaxel-eluting stent group, multiple stents were required in 57 patients (29.2%), with median Follow-up at 9 months was complete in 194 patients in the VBT group and 191 patients in the paclitaxel-eluting stent group (96.5% and 97.9%, respectively). For VBT and paclitaxel-eluting stents, respectively , the number of events and 9-month rates for ischemic target lesion revascularization were 27 (13.9%) vs 12 (6.3%) (relative risk [RR], 0.45; 95% confidence interval [CI], 0.24-0.86; P = .01); for ischemic target vessel revascularization, 34 (17.5%) vs 20 (10.5%) (RR, 0.60; 95% CI, 0.3 6-1.00; P = .046); and for overall major adverse cardiac events, 39 (20.1%) vs 22 (11.5%) (RR, 0.57; 95% CI, 0.35-0.93; P = .02) of cardiac death or myocardial infarction (10 [5.2%] vs 7 [3.7%]; RR, 0.71; 95% CI, 0.28-1.83; P = .48) and target vessel thrombosis Angiographic restenosis at 9 months was 31.2% (53 of 170 patients) with VBT and 14.5% (25 of 172 patients) with paclitaxel-eluting Stents (RR, 0.47; 95% CI, 0.30-0.71; P <.001). Conclusion: Treatment of bare-metal in-stent restenotic lesions with paclitaxel-eluting stents rather than angioplasty followed by VBT reduces clinical and angiographic restenosis at 9 months and improves event-free survival. Trial Registration: ClinicalTrials. gov Identifier: NCT00287573.