The Main Hospital operating rooms at Children’s Hospital of Philadelphia identified a decrease in hand hygiene compliance during the second half of fiscal year (FY) 2017. To address this, a combined approach of Human Factors and process improvement methodologies was used to increase compliance, with a global aim of achieving 100% compliance by the end of FY 2018. The Human Factors and Performance Improvement team relied upon a combined approached of methodologies and tools including: the SEEV model (Saliency, Effort, Expectancy, and Value), in-person observation, spaghetti diagrams, link analyses, and a survey to gain qualitative and quantitative data to drive the improvement work. Targeted interventions increased hand hygiene compliance in two pilot rooms by nearly 23%; following spread to the rest of the operating rooms, overall compliance was measured at 100%.