Abstract Objectives The Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 trial tested the feasibility of prehospital initiation of the bolus fibrinolytic reteplase (rPA) and determined the time saved by prehospital rPA in the setting of contemporary emergency cardiac care. Background Newer bolus fibrinolytics have undergone only limited evaluation for prehospital administration. In addition, as door-to-drug times have decreased, the relevance of findings from prior trials of prehospital fibrinolysis has become less certain. Methods Patients (n = 315) with ST-elevation myocardial infarction (STEMI) were enrolled in 20 emergency medical systems in North America. The time from emergency medical service (EMS) arrival to administration of a fibrinolytic was compared between study patients receiving prehospital rPA and sequential control patients from 6 to 12 months before the study who received a fibrinolytic in the hospital. Results Acute myocardial infarction was confirmed in 98%. The median time from EMS arrival to initiation of rPA was 31 min (25th to 75th percentile, 24 min to 37 min). The time from EMS arrival to in-hospital fibrinolytic for 630 control patients was 63 min (25th to 75th percentile, 48 min to 89 min), resulting in a time saved of 32 min (p < 0.0001). By 30 min after first medical contact, 49% of study patients had received the first bolus of fibrinolytic compared with only 5% of controls (p < 0.0001). In-hospital mortality was 4.7%. Intracranial hemorrhage occurred in 1.0%. Conclusions Prehospital administration of rPA is a feasible approach to accelerating reperfusion in patients with STEMI. Valuable time savings can be achieved in the setting of contemporary transport and door-to-drug times and may translate into an improvement in clinical outcomes.