Background: To improve patient outcomes, the Center for Medicare and Medicaid Services (CMS) implemented core measures that outline the initial treatment of the septic patient. These measures include initial blood culture collection prior to antibiotics, adequate intravenous fluid resuscitation, and early administration of broad spectrum antibiotics. We sought to determine if Paramedics can initiate the CMS sepsis core measure bundle in the prehospital field reliably. Methods: This is a retrospective, case series from a 3rd service EMS system model in Greenville, South Carolina between November 17, 2014 and February 20, 2016. An adult Prehospital Sepsis Assessment Tool was created using the 2012 Surviving Sepsis guidelines: 2 of 3 signs of systemic inflammatory response (heart rate, respiratory rate, oral temperature) and a known or suspected source of infection. A Sepsis Alert was called by paramedics and upon IV access a set of blood cultures and blood for lactate analysis was collected prior to field antibiotic administration. The Sepsis Alert was compared to serum lactate levels and ICD 9 or 10 admitting diagnosis of Sepsis, Severe Sepsis, or Septic Shock. Blood culture contamination, serum lactate, and antibiotic match were determined by in-hospital laboratory analysis. Results: A total of 120 trained paramedics called 1,185 Sepsis Alerts on 56,643 patients (50.3% Male, mean age 70). Patients with missing discharge diagnosis were eliminated (n = 31). The admitting diagnosis of sepsis overall was 73.5% (848/1154): Sepsis 50% (578/1154), Severe Sepsis 14.6% (169/1154), Septic Shock 8.9% (101/1154). A total of 946 blood cultures were collected in the prehospital setting, with a 95.04% (899/946) no contamination rate. Contamination was found in 4.96% (47/946). A total of 179 (18.9%) of the uncontaminated blood cultures were found to have positive growth with 720 (76.1%) having no growth. EMS administered antibiotics matched blood culture positive growth in 72% of patients. The lactate level was greater than 2.2 in 46.9% of patients. No adverse effects were reported after prehospital administration of antibiotics. Conclusion: This study demonstrates the successful implementation of an EMS-driven CMS Sepsis Core Measure bundle in the prehospital setting. Paramedics can acquire uncontaminated blood cultures, and safely administer antibiotics prior to hospital arrival among patients who were recognized as sepsis alerts.