Background: In 2019, a comprehensive cancer center was audited by a regulatory agency that identified opportunities to improve the safe delivery of healthcare. Even though the organization has been engaged in multiple continuous improvement initiatives, we found that to run a complex enterprise efficiently, we needed to break silos, learn from the frontline, and educate and train leaders in a psychologically safe environment. The overarching goal is to improve our culture of safety by developing a safety-focused workforce, improving robust processes around high-harm events, increasing transparency/feedback regarding safety events, and advancing the institution towards a High Reliability Organization (HRO)1 with zero preventable patient harm. Methods: Key interventions implemented: 1. Revamped our Root Cause Analysis; 2. Developed a Quality Assurance Performance Improvement (QAPI)2 council with leadership from the enterprise and representatives of the Patient Family Advisory Program, patients of the organization; 3. Implemented a Tiered Readiness Briefing (TRB) 7 days a week; 4. Selection of Serious Safety Event Rate (SSER)3 as the organization's measurement of patient safety and made it transparent; 5. Implementation of a mandatory training program in HRO skills and tools necessary to change behaviour. Training of leadership first goal was to get their buy-in so that the rest of the workforce would comply with the training; 6. Created Priority Focus Areas (PFA) initiatives supported by QAPI, the board, and leadership- providing resources to improve widespread, problem-prone, high-risk issues. Also, a system of accountability. Results: From June 2020 to April 2023- 59% reduction on SSER and sustained rate <0.9; 96% of leaders and 86% of medical faculty trained in HRO; 100% of “Start the Clock” issues identified in TRB are acted on within 24 hrs.; PFA success: the creation of the Blood Shortage Safety Decision Matrix- resulted in no surgery cancellation due to blood shortage. Conclusions: Rigorously implementing HRO principles in a comprehensive and complex cancer center resulted in improved process outcomes and patient safety outcomes that significantly reduced serious safety events. References: 1. Veazie S, Peterson K, Bourne D. Evidence Brief: Implementation of High Reliability Organization Principles. Washington (DC): Department of Veterans Affairs (US); 2019 May. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542883/; 2. Center for Medicare and Medicaid (2021, December 1). QAPI Description and Background. CMS.gov. https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/QAPI/qapidefinition; 3. Donnelly LF, Uhlhorn E, Bargmann-Losche J, Platchek TS. Serious Experience Events: Applying Patient Safety Concepts to Improve Patient Experience. J Patient Exp. 2022 May 23; 9:23743735221102670. doi: 10.1177/23743735221102670. PMID: 35647270; PMCID: PMC9134394.