Preventable patient safety problems continue to challenge health care organizations. This report describes a quality improvement intervention to reduce preventable harm in a 15-hospital health system using benchmarks, multidisciplinary teams, and evidence-based practices. The health system sought to prevent pressure ulcers, adverse drug events, falls with injury, health care–associated infections, and venous thromboembolism. Through leadership efforts and frontline engagement, they were able to realize substantial improvements during the initial 5-year period and achieve further reductions in adverse events during the subsequent 5 years. A PSNet perspective discussed efforts to address preventable health care–associated infections, including federal initiatives and further research avenues to consider.