BACKGROUND: Final results for the primary endpoint of the COVID-19 Monoclonal antibody Efficacy Trial-Intent to Care Early (COMET-ICE) randomized controlled trial (NCT04545060) showed a 79% (P < 0.001) adjusted relative risk reduction in longer-than-24-hour hospitalization or death due to any cause in high-risk patients with COVID-19 receiving sotrovimab compared with placebo at Day 29. Given the substantial costs associated with COVID-19 hospitalizations, there is a need to quantify the economic impact of clinical trial outcomes to inform decisionmaking. OBJECTIVE: To compare longer-than-24-hour hospitalization costs (primary objective) and total health care costs (secondary objective) associated with COVID-19 care in the sotrovimab vs placebo group in the COMET-ICE trial. METHODS: This was a 2-step, retrospective, post hoc, within-trial economic analysis. Step 1 was a health care claims (MarketScan) database analysis to source unit cost data (2020 USD) from a US payer perspective for COVID-19 care-related resource use from April 1 through June 30, 2020, among adults diagnosed with COVID-19 at high risk of progression (similar to those enrolled in the COMET-ICE trial). Cost per day for an inpatient event stratified by the following maximum respiratory support levels was obtained: no respiratory support or oxygen therapy only, noninvasive ventilation, and invasive mechanical ventilation. Cost per event was obtained for outpatient resource use. Step 2 was the within-trial economic analysis, in which unit costs from Step 1 were applied to the resource use (based on maximum respiratory support and length of stay for inpatient events and number of visits for outpatient events) observed during the first 29 days post-randomization in COMET-ICE. RESULTS: A total of 1,057 patients from the intent-to-treat COMET-ICE population were included (sotrovimab, n = 528; placebo, n = 529). Baseline demographic and clinical characteristics were well balanced between groups. During 29 days of follow-up, mean (SD) costs for the primary endpoint, longer-than-24-hour hospitalization, were $2,827 ($15,545) in the placebo group and $485 ($5,049) in the sotrovimab group (difference, -$2,342; P < 0.0001). Total health care costs were $2,850 ($15,546) in the placebo group and $525 ($5,070) in the sotrovimab group (difference, -$2,325; P = 0.0021). CONCLUSIONS: This post hoc within-trial economic analysis of COMET-ICE data shows that early treatment with sotrovimab vs placebo may be associated with lower longer-than-24-hour hospitalization costs and total health care costs for COVID-19 care in high-risk patients with COVID-19. These findings may be important in informing decision-making regarding use of sotrovimab in clinical practice. DISCLOSURES: Dr Lokhandwala and Ms Farrelly are employees of Xcenda LLC; Xcenda received funding from GSK to support the conduct of this study and did not receive funding for manuscript development. Mr Acharya and Dr Coutinho were employees of Xcenda LLC during the conduct of the study. Mr Bell and Dr Svedsater are employees of, and hold stocks/shares in, GSK. This study was funded by GSK (study 216974) and Vir Biotechnology, Inc. The study sponsors were involved in the study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.