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Introduction: The coronavirus 2019 (COVID-19) pandemic not only exacerbated barriers to healthcare but has also highlighted the trend toward increased vaccine hesitancy. Our goal was to improve COVID-19 vaccine uptake through a student-led, emergency department-based (ED) vaccination program. Methods: This prospective, quality-improvement pilot program used medical and pharmacy student volunteers as COVID-19 vaccine screeners in a southern, urban, academic ED. Patients eligible for vaccination were offered either the Janssen-Johnson & Johnson or the Pfizer-BioNTech COVID-19 vaccine and were educated about vaccine concerns. Vaccine acceptance rates were recorded, as well as reasons for vaccine hesitancy, vaccine brand preferences, and demographics. The primary and secondary quantitative outcomes were overall vaccine acceptance and change in vaccine acceptance after student-provided education, respectively. We performed logistic regression to identify potential variables that correlated with vaccine acceptance. Guided by the Consolidated Framework for Implementation Research, focus group interviews with four key stakeholder groups explored implementation facilitators and barriers. Results: We screened 406 patients for COVID-19 vaccination eligibility and current vaccine status, the majority of whom were unvaccinated. Of unvaccinated or partially vaccinated patients, vaccine acceptance before education was 28.3% (81/286), and vaccine acceptance after education was 31.5% (90/286) (% difference, 3.1% [95% CI 0.3%-5.9%], P=0.03). The most common hesitancy factors cited were concerns about side effects and safety. Results from the regression analysis indicated that increasing age and Black race were associated with an increased odds of vaccine acceptance. Focus groups revealed implementation barriers, including patient resistance and workflow issues, and facilitators, including student involvement and public health promotion. Conclusion: Using medical and pharmacy student volunteers as COVID-19 vaccine screeners was successful, and brief education provided by the students led to a modest increase in vaccine acceptance, with overall acceptance of 31.5%. Numerous educational benefits are described. [ABSTRACT FROM AUTHOR]