In patients with ST-segment elevation myocardial infarction (STEMI), the restoration of normal epicardial flow following fibrinolytic administration is associated with improved clinical outcomes. The goal of this analysis was to examine the relation between hyperemic flow and outcomes following fibrinolytic administration for STEMI. In Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28), patients with STEMI (n=3,491) treated with fibrinolytic therapy were scheduled to undergo angiography 48 to 192 hours after randomization. Corrected TIMI frame count (CTFC) and TIMI myocardial perfusion grade (TMPG) were assessed, and their associations with outcomes at 30 days were evaluated. When evaluating initial angiography of the infarct-related artery, there was a nearly linear relation between CTFC and 30-day mortality, with faster flow (lower CTFC) associated with improved outcomes. Conversely, in patients who underwent percutaneous coronary intervention (PCI), very fast flow (CTFC<14) after intervention was associated with worse outcomes. Post-PCI hyperemic flow (CTFC<14) was associated with a higher incidence of mortality (p=0.056), recurrent myocardial infarction (p=0.011), and a composite of death or myocardial infarction (p<0.001) compared with normal flow (CTFC 14 to 28). When post-PCI CTFC was further stratified by TMPG, there was a U-shaped relation between mortality and CTFC in patients with poor myocardial perfusion (TMPG 0 or 1). This relation appeared to be linear in patients with TMPG 2 or 3. In conclusion, in patients who undergo PCI after fibrinolytic therapy for STEMI, hyperemic flow on coronary angiography is associated with an increased incidence of adverse outcomes. Hyperemic flow with associated impaired myocardial perfusion may be a marker of more extensive downstream microembolization.