The increasing usage of peripherally inserted central catheters (PICCs) in medical imaging departments has led to a corresponding increase in cases of central line-associated bloodstream infection (CLABSI). However, this condition is preventable with proper monitoring and use of aseptic techniques. A Comprehensive Unit-based Safety Program (CUSP) is a quality improvement (QI) measure implemented by health care institutions to reduce the incidence of CLABSI. However, effective strategies have yet to be established. The authors describe a QI project that evaluated the implementation of CUSP at a teaching hospital to reduce PICC-associated bloodstream infection (BSI). The framework consists of a five-step process: understand and train staff on the science of safety, assemble a team, engage senior executives, identify defects through sensemaking, and implement teamwork and communication strategies in a series of related and sequential steps that use QI tools. Targets were identified for improvement from existing processes, and the workflow was reengineered. Nine months after the start of the CUSP intervention, PICC-associated BSI incidence in the hospital had been reduced from 3.4 to 2.7 per 1000 central lines days after intervention. The incidence of BSI was also reduced correspondingly from 8.8% to 5.9%. The QI processes in this study may be adopted by other hospitals, as they involve minimal cost with significant impact on patient safety and well-being. The QI sequential steps described capture the implementation processes that can be modified for use in other department settings where patient safety could be compromised. Online supplemental material is available for this article. ©RSNA, 2022.