Abstract: European Journal of Epidemiology https://doi.org/10.1007/s10654-022-00891-4 REVIEW Systematic review and meta-analysis of randomized trials of hydroxychloroquine for the prevention of COVID-19 Xabier García-Albéniz1,2 · Julia del Amo3 · Rosa Polo3 · José Miguel Morales-Asencio4 · Miguel A Hernán2,5,6 Received: 31 January 2022 / Accepted: 16 June 2022 © Springer Nature B.V. 2022 Abstract Background Recruitment into randomized trials of hydroxychloroquine (HCQ) for prevention of COVID-19 has been adversely affected by a widespread conviction that HCQ is not effective for prevention. In the absence of an updated systematic review, we conducted a meta-analysis of randomized trials that study the effectiveness of HCQ to prevent COVID-19. Methods A search of PubMed, medRxiv, and clinicaltrials.gov combined with expert consultation found 11 completed randomized trials: 7 pre-exposure prophylaxis trials and 4 post-exposure prophylaxis trials. We obtained or calculated the risk ratio of COVID-19 diagnosis for assignment to HCQ versus no HCQ (either placebo or usual care) for each trial, and then pooled the risk ratio estimates. Results The pooled risk ratio estimate of the pre-exposure prophylaxis trials was 0.72 (95% CI: 0.58–0.90) when using either a fixed effect or a standard random effects approach, and 0.72 (95% CI: 0.55–0.95) when using a conservative modification of the Hartung-Knapp random effects approach. The corresponding estimates for the post-exposure prophylaxis trials were 0.91 (95% CI: 0.72–1.16) and 0.91 (95% CI: 0.62–1.35). All trials found a similar rate of serious adverse effects in the HCQ and no HCQ groups. Discussion A benefit of HCQ as prophylaxis for COVID-19 cannot be ruled out based on the available evidence from randomized trials. However, the “not statistically significant” findings from early prophylaxis trials were widely interpreted as definite evidence of lack of effectiveness of HCQ. This interpretation disrupted the timely completion of the remaining trials and thus the generation of precise estimates for pandemic management before the development of vaccines. Background Xabier García-Albéniz xgarcia@rti.org 1 RTI Health Solutions, Av. Diagonal, 605, 9-1, 08028 Barcelona, Spain 2 CAUSALab. Harvard T.H. Chan School of Public Health, Boston, MA, USA 3 Division for HIV, STI, Viral Hepatitis and TB Control. Ministry of Health, Madrid, Spain 4 Department of Nursing and Podiatry, Instituto de Investigacion Biomedica de Malaga, Universidad de Málaga, Málaga, Spain 5 Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA 6 Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA Hydroxychloroquine (HCQ) is not an effective treatment for established coronavirus disease 2019 (COVID-19) [1, 2], but it is unclear whether HCQ can prevent symptomatic COVID-19. Early in the SARS-CoV-2 pandemic, about 30 randomized trials were designed to study HCQ as prophylaxis for COVID-19 [3]. After the findings from two of these trials were reported in the Summer of 2020 [4, 5], HCQ was generally viewed by the medical community as ineffective for COVID-19 prophylaxis. The emergence of that consensus was surprising because both trials found a lower risk of COVID-19 in the HCQ group, though they were too small to rule out either benefit or harm of HCQ. A timely completion of the remaining trials would have generated precise estimates of the potential..