Progress has been achieved in several areas of patient safety, but the cost-effectiveness of successful interventions remains an important question for policymakers and organizational leadership. This systematic review evaluated the cost-effectiveness of interventions to address 15 key safety targets (including health care–associated infections, adverse drug events, retained foreign bodies after surgery, and wrong-site surgery), but identified only 7 methodologically adequate economic analyses. Based on this limited dataset, the authors identified 4 cost-effective safety interventions, including checklists to prevent catheter-related bloodstream infections and medication reconciliation conducted by pharmacists. More robust economic analyses will be required in order to help prioritize safety interventions in the future.