Abstract: Clinical Infectious Diseases Major Article Ivermectin for the Treatment of Coronavirus Disease 2019: A Systematic Review and Meta-analysis of Randomized Controlled Trials 1 Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, Connecticut, USA; 2Universidad Científica del Sur, Lima, Peru; 3Centro de Investigación, Instituto Peruano de Oncología y Radioterapia, San Isidro, Lima, Peru; 4Cello Health, Yardley, Pennsylvania, USA; 5Unidad de Revisiones Sistemáticas y Meta-análisis, Guías de Práctica Clínica y Evaluaciones de Tecnologías Sanitarias (URSIGET), Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, La Molina, Lima, Peru; 6Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; 7Department of Neurology, Instituto de Infectologia Emílio Ribas, São Paulo, Brazil; and 8Laboratory of Medical Investigation, Unit 49, Hospital das Clinicas, Universidade de São Paulo, São Paulo, Brazil Background. We systematically assessed benefits and harms of the use of ivermectin (IVM) in patients with coronavirus disease 2019 (COVID-19). Methods. Published and preprint randomized controlled trials (RCTs) assessing the effects of IVM on adult patients with COVID-19 were searched until 22 March 2021 in 5 engines. Primary outcomes were all-cause mortality rate, length of hospital stay (LOS), and adverse events (AEs). Secondary outcomes included viral clearance and severe AEs (SAEs). The risk of bias (RoB) was evaluated using the Cochrane Risk of Bias 2.0 tool. Inverse variance random effect meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. Results. Ten RCTs (n = 1173) were included. The controls were the standard of care in 5 RCTs and placebo in 5. COVID-19 disease severity was mild in 8 RCTs, moderate in 1, and mild and moderate in 1. IVM did not reduce all-cause mortality rates compared with controls (relative risk [RR], 0.37 [95% confidence interval, .12–1.13]; very low QoE) or LOS compared with controls (mean difference, 0.72 days [95% confidence interval, −.86 to 2.29 days]; very low QoE). AEs, SAEs, and viral clearance were similar between IVM and control groups (low QoE for all outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality rates in 3 RCTs at high RoB were reduced with IVM. Conclusions. Compared with the standard of care or placebo, IVM did not reduce all-cause mortality, LOS, or viral clearance in RCTs in patients with mostly mild COVID-19. IVM did not have an effect on AEs or SAEs and is not a viable option to treat patients with COVID-19. Keywords. ivermectin; SARS-CoV-2; COVID-19; mortality; meta-analysis. The coronavirus disease 2019 (COVID-19) pandemic represents a global sanitary, social, and economic challenge. However, scientific advances have also amplified deficiencies and misinformation [1]. Biological plausibility, pathophysiological considerations, in vitro research, observational studies, and/or clinical trials with heterogeneous quality were used to evaluate several repurposed drugs repurposed for indications different from the approved ones. Some policy makers and regulatory institutions authorized emergency use of unproven COVID-19 treatments; the use of some of these treatments has been heavily politicized in some regions [2, 3]. Ivermectin (IVM) is a semisynthetic,..