Background After successful thrombolysis, a high-grade stenosis at 24-hour angiography is strongly predictive of reocclusion and is often believed to result in high reinfarction rates. However, routine angioplasty did not reduce death or reinfarction in past trials. Systematic angiographic follow-up shows that reocclusion often occurs without clinical reinfarction. This study investigates whether the increased risk for reocclusion associated with a high-grade lesion translates into impaired clinical outcome. Methods In the ischemia-guided Antithrombotics in the Prevention of Reocclusion in COronary Thrombolysis (APRICOT-1) trial, 240 patients with ST-elevation MI who had an open infarct artery 24 hours after thrombolysis had 3-month repeat angiography to assess reocclusion, with clinical follow-up at 3 months and 3 years. Results On the basis of the optimal discriminative stenosis severity, the reocclusion rate was 40% (47/118) in patients with a high-grade residual stenosis and 16% (20/122) in patients with a low-medium-grade lesion (risk ratio [RR], 2.43; 95% CI, 1.54–3.84; P <.01). Three-month death and reinfarction rates did not differ: 6% (7/118) versus 9% (11/122; RR, 0.66; 95% CI, 0.26–1.64; P = not significant). Systematic angiographic follow-up revealed that reocclusion of a high-grade lesion occurred in the absence of clinical reinfarction in 85% (40/47) of patients, as compared with 45% (9/20) in patients with a low-medium-grade stenosis (RR, 1.89; 95% CI, 1.15–3.12; P <.01). Despite an independent association with reocclusion, a high-grade stenosis was not predictive of either short- or long-term death and reinfarction. Conclusions After successful thrombolysis and adopting an ischemia-guided revascularization strategy, patients with a high-grade stenosis experience death/reinfarction rates similar to that of patients with a low-medium-grade lesion. This is true despite a 2- to 3-fold higher risk for reocclusion. The finding that reocclusion of a high-grade lesion often occurs without clinical reinfarction explains the absence of a relationship between a severe stenosis and death/reinfarction. Appreciation of these observations may contribute to an optimal design of a future randomized trial to re-evaluate the impact of a routine invasive strategy.