OBJECTIVES: This study aims to advance patient safety science by identifying and addressing the systemic causes of psychosocial harm among transgender and gender nonbinary (TGNB) individuals. The 4-year TRANS-SAFE patient safety learning laboratory (PSLL) will follow a 6-phase systems engineering approach to study ways to improve the safety of TGNB patients. METHODS: This study involves conducting a systematic scoping review, interviews with patients, providers, and community members, and observations of TGNB patient and provider experiences to identify determinants of avoidable patient suffering. In addition, the PSLL will provide financial support for pre-doctorate and post-doctorate research scholars in the TGNB community. Human-centered solutions will be co-designed to mitigate psychosocial harm among TGNB individuals. Interventions will be developed through engagement with stakeholders in an iterative process of co-design and evaluation. RESULTS: Interventions will be evaluated in real and simulated clinical environments for effectiveness, acceptability, usability, feasibility of implementation, and sustainability. A structural innovation of this PSLL is its focus on sustainment and dissemination, which will be facilitated through the development of a TRANS-SAFE certification process for health care organizations in partnership with the World Professional Association for Transgender Health (WPATH). CONCLUSIONS: This PSLL will address a fundamental gap in the science and practice of patient safety by assessing and addressing psychosocial patient harm in a high-risk population that has been too often neglected in the patient safety literature.