Central line–associated bloodstream infections are considered to be an avoidable complication of care delivery. In addition to considerable morbidity and use of resources, central line–associated bloodstream infections carry an attributable morality between 12% and 25%. The estimated cost per infection is approximately $25000. Research over the last decade has focused on a number of care activities that have been shown to reduce the incidence of bloodstream infections related to central line placement in the critically ill patient. A significant reduction or elimination of central line-associated bloodstream infections can occur with implementation of a comprehensive central line–associated bloodstream infection prevention program that includes staff education, hand hygiene, use of maximal sterile barrier precautions, chlorhexidine gluconate skin antisepsis, avoidance of femoral lines, empowerment of staff to stop the procedure if sterile technique is broken, and daily assessment of the continued need for a central line. This article focuses on strategies for implementing a comprehensive central line–associated bloodstream infections prevention program and a tool and process for defect analysis as part of a statewide collaborative in Michigan.