Following primary percutaneous coronary intervention (PPCI) for ST segment elevation myocardial infarction, microvascular perfusion is often impaired secondary to thrombotic embolization. Intracoronary (IC) fibrinolytic administration may reduce thrombotic burden and distal embolization. The ICE-T-TIMI-49 study evaluated the feasibility and safety of low-dose IC tenecteplase (TNK) during PPCI. The study randomized 40 PPCI patients to a volume matched bolus of IC TNK (4 mg) (n = 20) or IC saline placebo (n = 20) before and following PPCI. The primary end point was percent diameter stenosis of the culprit lesion following first bolus. The primary end point did not differ between IC placebo (median 100%, interquartile range [IQR] 83.0,100.0) and IC TNK (median 100% stenosis, IQR 91.0,100.0; p = 0.522). However, the proportion of patients with reduction in thrombus following first bolus tended to be greater with IC TNK (placebo: 12.5% vs IC TNK: 40.0%, p = 0.133). Following PPCI, the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count (cTFC) was lower (faster) with placebo (16.0 frames [IQR 12.0,24.0] vs 24.0 frames [22.0,32.0], p = 0.045) due to a trend towards greater frequency of hyperemia (cTFC <14), a marker of distal embolization (50.0% vs 8.3%, p = 0.056). There was no difference in TIMI major bleeds and no intracranial hemorrhage. In conclusion, treatment with low-dose IC TNK appears safe and well tolerated during PPCI. Although IC TNK administration did not improve percent stenosis, a trend towards reduced thrombus burden was demonstrated with less hyperemia (a marker of distal embolization). Our findings provide support for a large randomized study.