Introduction: Central Line-Associated Bloodstream Infections (CLABSI) are the largest contributor to harm across the Children's Hospital's Solutions for Patient Safety network. Pediatric hematology/oncology (PHO) patients are at increased risk for CLABSI due to multiple factors. Consequently, traditional CLABSI prevention strategies are insufficient to eliminate CLABSI in this high-risk population. Methods: Our SMART aim was to reduce the CLABSI rate by 50% from a baseline of 1.89/1000 central line days to less than 0.9/1000 central line days by December 31, 2021. We created a multidisciplinary team being mindful to identify roles and responsibilities upfront. We developed a key driver diagram and designed and implemented interventions to influence our primary outcome. Results: We implemented interventions and conducted Plan-Do-Study-Act cycles concurrently. We found that performing audits by directly observing tasks rather than auditing documentation resulted in more accurate compliance assessments. As a result, our CLABSI rate improved from 1.89/1000 central line days in 2020 with 11 primary CLABSI to 0.73/1000 central line days in 2021 with four primary CLABSI. Average days between events improved from 30 days in 2020 to 73 days in 2021, and we achieved an unprecedented 542 days CLABSI-free, extending into 2022. Conclusions: Through a multimodal approach and utilizing characteristics of high-reliability organizations, we significantly reduced primary CLABSI, approaching zero in our PHO population and doubling the average days between events. Future efforts will focus on the sustained engagement of all stakeholders and improving our safety culture.