Ambulatory central line-associated bloodstream infections (CLABSIs) cause significant morbidity and mortality, especially in pediatric oncology. Few studies have had interventions directed toward caregivers managing central lines (CL) at home to reduce ambulatory CLABSI rates. We aimed to reduce and sustain our ambulatory CLABSI rate by 25% within 3years of the start of a quality improvement intervention. Plan-do-study-act cycles were implemented beginning April 2016. The main intervention was a family-centered CL care skill development curriculum for external CLs. Training began upon hospital CL insertion, followed by an ambulatory teach-back program to achieve home caregiver CL care independence. Other changes included: standardizing ambulatory nurse CL care practice (audits, a train the nurse trainer process, and workshops for independent home care agencies); developing aids for trainers and caregivers; providing supplies for clean surfaces; wide dissemination of the program; and minimizing opportunities of CLABSI (e.g., standardizing timing of CL removal). The outcome measure was the ambulatory CLABSI rate (excluding mucosal barrier injury laboratory-confirmed bloodstream infection), compared pre intervention (January 2015 to March 2016) to post intervention, including 2years of sustainability (April 2016 to June 2023), using statistical process control charts. We estimated the total number of CLABSI and associated healthcare charges prevented. The ambulatory CLABSI rate decreased by 52% from 0.25 to 0.12 per 1000 CL days post intervention, achieved within 27months; 117 CLABSI were prevented, with $4.2 million hospital charges and 702 hospital days avoided. Focusing efforts on home caregivers CL care may lead to reduction in pediatric oncology ambulatory CLABSI rates.