Speed of reperfusion is critical in ST-segment elevation myocardial infarction (STEMI). We assessed the safety and feasibility of an integrated metropolitan approach in which advanced-care paramedics interpret the prehospital electrocardiogram and independently refer patients with STEMI to a designated center for primary percutaneous coronary intervention (PCI). We developed and implemented a protocol in which paramedics trained in electrocardiographic interpretation bypassed the nearest emergency room and referred patients with suspected STEMI directly to a designated primary PCI center (paramedic-referred primary PCI). Outcomes of these patients were compared with those of a retrospective cohort of 225 consecutive patients with STEMI transported by ambulance to the nearest hospital emergency department. We treated 108 consecutive patients with STEMI using ambulance services according to the paramedic-referred primary PCI protocol. Primary PCI was performed in 93.5% versus 8.9% in the control group, and the median door-to-balloon time was 63 versus 125 minutes in the control group (p <0.0001 for 2 comparisons). Thrombolytic therapy was prescribed to 80.4% of the control group, with a median door-to-needle time of 41 minutes. In-hospital mortality was 1.9% in the paramedic-referred primary PCI group versus 8.9% in the control group (p = 0.017) and remained significantly lower after statistical adjustment for baseline risk. In conclusion, paramedic-referred primary PCI is a safe and feasible strategy for treating STEMI that is associated with rapid and effective reperfusion and very low in-hospital mortality.