Background: COVID-19 vaccine uptake by healthcare workers (HCWs) is critical to protect HCWs, the patients they care for, and the healthcare infrastructure. Our study aims to examine the actual COVID-19 vaccination rate among HCWs and identify risk factors associated with vaccine nonacceptance. Study Design and Methods: A retrospective analysis of COVID-19 vaccinations for HCWs at a large multi-site US academic medical center from 12/18/2020 through 05/04/2021. Comparisons between groups were performed using unpaired student t-test for continuous variables and the chi-square test for categorical variables. A logistic regression analysis was used to assess the associations between vaccine uptake and risk factor(s). Results: Of the 65,270 HCWs included in our analysis, the overall vaccination rate was 78.6%. Male gender, older age, White and Asian race, and direct patient care were associated with higher vaccination rates (P < .0001). Significant differences were observed between different job categories. Physicians and advanced practice staff, and healthcare professionals were more likely to be vaccinated than nurses and support staff. Conclusions: Our data demonstrated higher initial vaccination rates among HCWs than the general population national average during the study period. We observed significant disparities among different high-risk HCWs groups, especially among different job categories, black HCWs and younger HCWs despite their high risk of contracting the infection. Interventions to address lower vaccination rate and vaccine hesitancy should be built with these disparities and differences in mind to create more targeted interventions.