BACKGROUND: Although considered the highest level of evidence and critical-to-test novel therapies, clinical trials are unrepresentative of the "real world" as they lack a true patient denominator, which limits general applicability of results. Accordingly, in conjunction with the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen 3+ trial, we evaluated a comprehensive contemporary cohort of patients with ST segment elevation myocardial infarction (STEMI) to investigate: feasibility, applicability, safety, and efficacy of de novo paramedic-based prehospital fibrinolysis (PHF) program. METHODS: Prospective observational comparative cohort of all patients with STEMI encountered during the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen 3+ enrollment period. Time-to-treatment, systematic electrocardiographic (ECG) analysis, peak creatine kinase, inhospital clinical events, and mortality were assessed. RESULTS: During the 22-month study period, 1095 patients with STEMI were admitted to hospital; 46% (119/258) of eligible patients received PHF (< or = 6 hours of symptom onset by ambulance). Paramedics contacted the study physician 3.6 times per week: 33% (119/357) of patients enrolled, and ECG transmission failure is 6%. Time-to-treatment was reduced with PHF versus inhospital (1 hour 43 minutes vs 2 hours 38 minutes; P < .001). Despite higher baseline Thrombolysis in Myocardial Infarction Scores and greater ECG territory at risk (ST), prehospital patients achieved more favorable outcomes: peak creatine kinase (1413 vs 1549 U/L; P = .122), Q wave at discharge (56.3% vs 70.7%; P = .003), and intracranial hemorrhage (0% vs 0.8%; P < 1.0), respectively. Inhospital mortality for PHF versus inhospital patients was 3.4% versus 4.8% (P = .627), with an adjusted odds ratio of 0.60 (confidence interval, 0.19-1.87). CONCLUSION: Feasibility and applicability of PHF was demonstrated with a substantial reduction in treatment delay and favorable clinical outcomes. Extending the unrealized potential of paramedic-based PHF programs in North America is feasible and desirable.