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OBJECTIVE: To investigate temporal trends and outcomes associated with early antibiotic prescribing in patients hospitalized with COVID-19. DESIGN: Retrospective propensity-matched cohort study using the National COVID Cohort Collaborative (N3C) database. SETTING: Sixty-six health systems throughout the United States that were contributing to the N3C database. Centers that had fewer than 500 admissions in their dataset were excluded. PATIENTS: Patients hospitalized with COVID-19 were included. Patients were defined to have early antibiotic use if they received at least 3 calendar days of intravenous antibiotics within the first 5 days of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 322,867 qualifying first hospitalizations, 43,089 patients received early empiric antibiotics. Antibiotic use declined across all centers in the data collection period, from March 2020 (23%) to June 2022 (9.6%). Average rates of early empiric antibiotic use (EEAU) also varied significantly between centers (deviance explained 7.33% vs 20.0%, p < 0.001). Antibiotic use decreased slightly by day 2 of hospitalization and was significantly reduced by day 5. Mechanical ventilation before day 2 (odds ratio [OR] 3.57; 95% CI, 3.42-3.72), extracorporeal membrane oxygenation before day 2 (OR 2.14; 95% CI, 1.75-2.61), and early vasopressor use (OR 1.85; 95% CI, 1.78-1.93) but not region of residence was associated with EEAU. After propensity matching, EEAU was associated with an increased risk for in-hospital mortality (OR 1.27; 95% CI, 1.23-1.33), prolonged mechanical ventilation (OR 1.65; 95% CI, 1.50-1.82), late broad-spectrum antibiotic exposure (OR 3.24; 95% CI, 2.99-3.52), and late Clostridium difficile infection (OR 1.60; 95% CI, 1.37-1.87). CONCLUSIONS: Although treatment of COVID-19 patients with empiric antibiotics has declined during the pandemic, the frequency of use remains high. There is significant inter-center variation in antibiotic prescribing practices and evidence of potential harm. Our findings are hypothesis-generating and future work should prospectively compare outcomes and adverse events. [ABSTRACT FROM AUTHOR]