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Abstract Background: Factors influencing excessive antimicrobial utilization in hospitalized patients remain poorly understood, particularly with the COVID-19 pandemic. Methods: In this retrospective cohort, we compared administrative data regarding antimicrobial prescriptions in hospitalized patients in South Carolina from March 2020 through September 2022. The study examined variables associated with antimicrobial use across demographics, COVID status, and length of stay, among other variables. Results: Significant relationships were seen with antimicrobial use in COVID-19 positive patients (OR 2.00, 95% Confidence Interval (CI): 1.9–2.1), young adults (OR 1.08, 95% CI: 0.99–1.12, COVID-19 positive Blacks and Hispanics (OR 1.06, 95% CI: 1.01–1.11, OR 1.05, 95% CI: 0.89–1.23), and COVID-19 positive patients with ≥2 comorbid conditions (OR 1.55, 95% CI: 1.43–1.68). Discussion: Further analysis in more than one healthcare system should explore these ecologic relationships further to understand if these are common trends to inform ongoing stewardship interventions.