Context: As many as 14% of patients transported by ambulance with chest pain die prior to hospital discharge. To date, no high-quality controlled trials have revealed that prehospital advanced life support interventions affect survival for these patients. Objective: The Ontario Prehospital Advanced Life Support (OPALS) Study assessed the effect of adding an advance life support service to an existing basic life support emergency medical service program, on the rate of mortality and morbidity for patients with out-of-hospital chest pain. Design: Controlled clinical trial comparing survival for 9 months before and 9 after instituting an advanced life support program. Setting: Thirteen urban and suburban Ontario communities (populations ranging from 30,000 to 750,000; total, 2.5 million). Patients: All adult patients with a primary complaint of chest pain and transported by paramedics to the emergency department. Intervention: Paramedics were trained in standard advanced life support, which includes endotracheal intubation, intravenous furosemide and morphine, oral ASA, and sublingual NTG. Emergency medical services within each community had to meet predefined criteria in order to qualify for the advanced life support phase. Main Outcome Measure: Survival to hospital discharge. Results: Overall, 12,168 patients were enrolled in either the basic life support phase (N = 5,788) or the advanced life support phase (N = 6,380). The rate of mortality significantly decreased from 4.3% in the basic life support phase to 3.2% in the advanced life support phase (absolute change 1.1, 95% CI 0.4-1.8, P = 0.0013). We also demonstrated a decrease in mortality for the subgroup of patients with a discharge diagnosis of myocardial infarction (13.1 percent vs 8.2 percent, P = 0.002). Conclusions: The addition of a prehospital advanced life support program to an existing basic life support emergency medical service was associated with a significant decrease in the mortality rate among patients complaining of chest pain. Future research should clarify the most effective interventions and target specific populations.