Abstract: Open Forum Infectious Diseases MAJOR ARTICLE Real-world Effectiveness and Tolerability of Monoclonal Antibody Therapy for Ambulatory Patients With Early COVID-19 Brandon J. Webb,1,2, Whitney Buckel,3 Todd Vento,1 Allison M. Butler,4 Nancy Grisel,4 Samuel M. Brown,5 Ithan D. Peltan,5 Emily S. Spivak,6 Mark Shah,7 Theadora Sakata,8 Anthony Wallin,8 Eddie Stenehjem,1,2,9 Greg Poulsen,10 and Joseph Bledsoe7,11 Background. Neutralizing monoclonal antibodies (MAbs) are a promising therapy for early coronavirus disease 2019 (COVID19), but their effectiveness has not been confirmed in a real-world setting. Methods. In this quasi-experimental pre-/postimplementation study, we estimated the effectiveness of MAb treatment within 7 days of symptom onset in high-risk ambulatory adults with COVID-19. The primary outcome was a composite of emergency department visits or hospitalizations within 14 days of positive test. Secondary outcomes included adverse events and 14-day mortality. The average treatment effect in the treated for MAb therapy was estimated using inverse probability of treatment weighting and the impact of MAb implementation using propensity-weighted interrupted time series analysis. Results. Pre-implementation (July–November 2020), 7404 qualifying patients were identified. Postimplementation (December 2020–January 2021), 594 patients received MAb treatment and 5536 did not. The primary outcome occurred in 75 (12.6%) MAb recipients, 1018 (18.4%) contemporaneous controls, and 1525 (20.6%) historical controls. MAb treatment was associated with decreased likelihood of emergency care or hospitalization (odds ratio, 0.69; 95% CI, 0.60–0.79). After implementation, the weighted probability that a given patient would require an emergency department visit or hospitalization decreased significantly (0.7% per day; 95% CI, 0.03%–0.10%). Mortality was 0.2% (n = 1) in the MAb group compared with 1.0% (n = 71) and 1.0% (n = 57) in pre- and postimplementation controls, respectively. Adverse events occurred in 7 (1.2%); 2 (0.3%) were considered serious. Conclusions. MAb treatment of high-risk ambulatory patients with early COVID-19 was well tolerated and likely effective at preventing the need for subsequent emergency department or hospital care. Keywords. novel coronavirus; COVID-19; SARS-CoV-2; monoclonal antibody; casirivimab; imdevimab; bamlanivimab. Monoclonal antibodies (MAbs) designed to avidly bind to the receptor binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein are an emerging neutralizing passive immune therapy for coronavirus disease 2019 (COVID-19). In fall 2020, bamlanivimab (Eli Lilly, Indianapolis, IN, USA) and casirivimab/imdevimab (Regeneron, Tarrytown, NY, USA) received US Food and Drug Received 21 April 2021; editorial decision 17 June 2021; accepted 19 June 2021. Correspondence: Brandon J. Webb, MD, Division of Epidemiology and Infectious Diseases, Intermountain Medical Center, 5121 S. Cottonwood Drive, Murray, UT 84157 (brandon.webb@ imail.org). Open Forum Infectious Diseases®2021 © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original..