Objective: Apply Human Factors (HF), systems engineering, and high reliability organizational principles to improve adverse event investigations in a regional hospital system. Background: Given the complexity of medicine and healthcare systems, innovative thinking is required to ensure these systems are resilient to error. Understanding the work system and its constituent parts is fundamental to understanding how errors begin and propagate. Method: This paper provides a discussion on employing a systems-based approach to improve perioperative adverse event investigations within a hospital system. Results: Data was collected across 13 investigations. The findings are summarized into 16 contributing factors, with 10 specific examples of critical/serious risks that were addressed by the hospital system. Conclusion: Modern medicine needs to look to HF to improve safety and reduce errors. This manuscript provides a systems-based approach grounded in HF and organizational theories to improve how investigations are conducted and the approach to human error within a large hospital system. Application: This work provides practical guidance for those who want to improve postoperative investigations within their own units or hospitals. Precis: This article describes research that evolves the approach to accident investigation to improve perioperative adverse event investigations in hospital settings.