Project Abstract Nearly 800,000 people in the United States (US) each year experience acute stroke, which remains the leading cause of adult disability and 5th leading cause of death. Despite the proliferation of stroke centers nationwide, almost half of the US population lives beyond a 60-minute drive of a comprehensive stroke center (CSC) and most patients are initially evaluated at a primary stroke center (PSC). While a key treatment, alteplase can be delivered at most US hospitals, advanced diagnostics and treatments are only available at CSCs. However, the PSC “Door-in-Door-Out” (DIDO) evaluation process for patients who need to be transferred to a CSC can be time consuming and inefficient, contributing to inability to receive treatment. Building upon our prior work to reduce PSC DIDO time, this proposal, “Implementation of a Stroke Protocol for Emergency Evaluation and Disposition (I-SPEED)” seeks to (1) Implement a novel, evidence-based, multi-component DIDO intervention in eight diverse stroke systems of care across multiple regions of the US and (2) Conduct a dual evaluation of its effectiveness in reducing median DIDO time (primary outcome) and disability (secondary outcome) and of the fidelity and quality of implementation. The I-SPEED study will definitively establish the effectiveness and generalizability of a multi-component evidence-based DIDO intervention and provide information about contextual adaptations for high-quality implementation and widespread dissemination. This study benefits from our well-established interdisciplinary expertise in stroke, emergency and prehospital medicine, systems and quality engineering, health services research, and strong multicenter research collaborations. Findings from I- SPEED will have substantial implications for a wide range of hospitals and stroke systems of care worldwide.