Preventing health care–associated infections remains a patient safety priority. This multisite study compared rates of central line–associated bloodstream infections, surgical site infections, and ventilator-associated pneumonia before and after implementation of a multifaceted intervention. Investigators adopted the comprehensive unit-based safety program, which emphasizes safety culture and includes staff education, identification of safety risks, leadership engagement, and team training. Central line–associated bloodstream infections and surgical site infections initially declined, but rates returned to baseline in the third year. They were unable to measure differences in ventilator-associated pneumonia rates due to a change in the definition. These results demonstrate the challenge of implementing and sustaining evidence-based safety practices in real-world clinical settings. A past PSNet interview discussed infection prevention and patient safety.