Background. Ventilator-associated pneumonia (VAP) has been a challenge for our burn, trauma, and neurosurgical population because of their underlying injuries, prolonged mechanical ventilation, need for spinal clearance prior to head-of-bed elevation, and risk for multidrug-resistant organisms, resulting in a total of 266 cases of VAPs in 2007. Intervention detail. We developed a multidisciplinary team, involving critical care, infection control, antimicrobial stewardship, clinical education, and information technology (IT), focused on prevention, diagnosis, and management with detailed surveillance of VAP cases and rates, microbiology, and antimicrobial resistance. Each VAP case is reviewed at the unit level with the multidisciplinary care team for VAP risk factors as well as bundle compliance. IT has facilitated electronic surveillance of bundle compliance in all ventilated patients as well as an automated daily list of all patients on spine precautions and time to head of bed >30°. Results. Improved antimicrobial use along with infection control initiatives such as hand hygiene, active surveillance cultures of all intensive care unit patients for MRSA and carbapenem-resistant Acinetobacter, use of contact precautions, daily chlorhexidine baths, and improved environmental cleaning with monthly audits have led to dramatic reductions in VAP caused by MRSA and Acinetobacter. Changes in local microbiology resulted in modification of empirical antimicrobial therapy and reduced use of imipenem for late-onset VAP (mechanical ventilation or hospitalization >5 days). In addition, active surveillance cultures have a 99% negative predictive value for the development of MRSA VAP, allowing more judicial use of empirical vancomycin. More appropriate use of vancomycin and imipenem are estimated to reduce pharmacy costs by $130 000 per year. These measures have led to a sustained reduction in the number of VAP cases from 266 in 2007 to 98 in 2010, reflecting a 63% reduction in the absolute number of VAP cases, and our management has been improved through appropriate antimicrobial therapy based on local microbiology and resistance patterns. © 2012 by the American College of Medical Quality.