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Little research has been done on the use of electronic health record–based clinical decision support (EHR CDS) to support antibiotic stewardship in the emergency department (ED).Workflow efficiency and decision-making authority shaped uptake of EHR CDS for antibiotic stewardship programs.Barriers included pace of ED, alert fatigue, and managing parents' expectations.Provider beliefs and institutional context influenced antibiotic decision-making.Specific principles and practices can enhance use of EHR CDS to support antibiotic stewardship programs.Antibiotic stewardship programs (ASPs) have not been fully developed for the emergency department (ED), in part the result of the barriers characteristic of this setting. Electronic health record–based clinical decision support (EHR CDS) represents a promising strategy to implement ASPs in the ED. We aimed to determine the cultural beliefs and structural barriers and facilitators to implementation of antimicrobial stewardship in the pediatric ED using EHR CDS.Interviews and focus groups were conducted with hospital and ED leadership, attending ED physicians, nurse practitioners, physician assistants, and residents at a single health system in Colorado. We reviewed and coded the data using constant comparative analysis and framework analysis until a final set of themes emerged.Two dominant perceptions shaped providers' perspectives on ASPs in the ED and EHR CDS: (1) maintaining workflow efficiency and (2) constrained decision-making autonomy. Clinicians identified structural barriers to ASPs, such as pace of the ED, and various beliefs that shaped patterns of practice, including accommodating the prescribing decisions of other providers and managing parental expectations. Recommendations to enhance uptake focused on designing a simple yet flexible user interface, providing clinicians with performance data, and on-boarding clinicians to enhance buy-in.Developing a successful ED-based ASP using EHR CDS should attend to technologic needs, the institutional context, and the cultural beliefs of practice associated with providers' antibiotic prescribing.