Abstract: Article Favipiravir in the Treatment of Outpatient COVID-19: A Multicenter, Randomized, Triple-Blind, Placebo-Controlled Clinical Trial Atefeh Vaezi 1 , Mehrzad Salmasi 2 , Forogh Soltaninejad 3 , Mehrdad Salahi 4, *, Shaghayegh Haghjooy Javanmard 5 and Babak Amra 3 1 2 3 4 5 * Cancer Prevention Research Center, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran Bamdad Respiratory and Sleep Research Center, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran Department of Infectious Disease, School of Medicine, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran Department of Physiology, Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran Correspondence: salahimehrdad@yahoo.com Highlights: What are the main findings? • Favipiravir, an RNA-dependent RNA polymerase inhibitor, shows no benefit in preventing the hospitalization of mild to moderate COVID-19 patients. What is the implication of the main finding? • Citation: Vaezi, A.; Salmasi, M.; Soltaninejad, F.; Salahi, M.; Javanmard, S.H.; Amra, B. Favipiravir in the Treatment of Outpatient COVID-19: A Multicenter, Randomized, Triple-Blind, Placebo-Controlled Clinical Trial. Adv. Respir. Med. 2023, 91, 18–25. https://doi.org/10.3390/arm91010004 Received: 28 November 2022 Revised: 11 January 2023 Accepted: 20 January 2023 Published: 28 January 2023 Copyright: © 2023 by the authors. Our results may inform decisions on the exclusion of Favipiravir from mild to moderate COVID-19 treatment guidelines. Abstract: Background: Finding effective outpatient treatments to prevent COVID-19 progression and hospitalization is necessary and is helpful in managing limited hospital resources. Repurposing previously existing treatments is highly desirable. In this study, we evaluate the efficacy of Favipiravir in the prevention of hospitalization in symptomatic COVID-19 patients who were not eligible for hospitalization. Methods: This study was a triple-blind randomized controlled trial conducted between 5 December 2020 and 31 March 2021 in three outpatient centers in Isfahan, Iran. Patients in the intervention group received Favipiravir 1600 mg daily for five days, and the control group received a placebo. Our primary outcome was the proportion of hospitalized participants from day 0 to day 28. The outcome was assessed on days 3, 7, 14, 21, and 28 through phone calls. Results: Seventy-seven patients were randomly allocated to Favipiravir and placebo groups. There was no significant difference between groups considering baseline characteristics. During the study period, 10.5% of patients in the Favipiravir group and 5.1% of patients in the placebo group were hospitalized, but there was no significant difference between them (p-value = 0.3). No adverse event was reported in the treatment group. Conclusions: Our study shows that Favipiravir did not reduce the hospitalization rate of mild to moderate COVID-19 patients in outpatient settings. Keywords: efficacy; Favipiravir; mild COVID-19; outpatient; SARS-CoV-2 Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license..