Introduction: In 2011 we observed that the 28-day mortality rate for sepsis at Thomas Jefferson University Hospital (TJUH) was significantly higher than the rate of the University Health System Consortium (UHC) (34% vs. 21%). We determined that changes would need to be made system-wide and across multiple departments and disciplines to significantly improve outcomes. Methods: An interdisciplinary committee was established which included physicians, nurses, pharmacists, administrators, and support staff from the Emergency Department (ED), the Medical Intensive Care Unit (MICU), Infectious Diseases (ID), and Information Services (IS). The committee examined each phase of sepsis recognition and treatment from first contact in the ED to eventual MICU transfer. Targeted education programs were developed specifically for physicians, nurses, and pharmacy staff. An electronic protocol was created to streamline the recognition and treatment of sepsis. The protocol created new standards for all providers in the care team. Innovations included automatic electronic alerts based on vital signs, First Line Orders (FLOs) for triage nurses, easy-to-use treatment order sets, stocking ED Pyxis® machines with all medications needed in the protocol, and intranet based resources allowing all staff to easily access the protocol. Continual process improvement is imperative to the initiative and the committee meets monthly to review performance. Results: All patients with a diagnosis-related group (DRG) code of sepsis were analyzed for 28-day mortality. Mortality in the six month time period before implementation of the sepsis protocol was 24.9% (n=170) compared with 16.23% (n=289) (p=0.049) in the six month time period post intervention. Reduction in the mortality-index (observed deaths TJUH/expected deaths UHC) from sepsis over was also reduced, from 1.31 in the pre-implentation period to 0.94 (p>0.05). Data on process measures associated with of optimal sepsis care were collected over a shorter two-month time period and compared to a sample of historical controls. Blood cultures were drawn before the administration of antibiotics 57.9% of the time prior to protocol initiation and 96.9% of the time after protocol initiation. The rate of early antibiotic administration increased from 57.9% pre-intervention to 84.4% after protocol initiation. Adequate fluid resuscitation in hypotensive patients increased from 62.5% to 93.8%. Initiation of vasopressors for persistent hypotension increased, from 23.1% to 77.8%. Data collection and analysis is ongoing. Conclusions: We report the successful development and implementation of a protocolized system for improved recognition and management of sepsis. With implementation of a targeted educational program and a protocolized system we were able to increase compliance with key interventions known to decrease mortality and morbidity, particularly aggressive fluid resuscitation and timely antibiotic therapy and ultimately significantly improve our outcomes. We believe that key elements to our success were: 1) Interdisciplinary and interdepartmental involvement of all the stakeholders in sepsis care 2) A targeted educational program emphasizing the importance of early recognition of sepsis and the value of protocolized care. 3) Close collaboration with IS to find new and innovative uses for our current EMRs, including the development of automated sepsis alerts to facilitate early recognition of patients at risk as well as bundled order sets 5) A process of continuous review of performance with regular feedback to practitioners.