Abstract: ARTICLE https://doi.org/10.1038/s41467-021-22446-z OPEN 1234567890():,; Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https:// osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2021)12:2349 | https://doi.org/10.1038/s41467-021-22446-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-22446-z C oronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential of progression into respiratory failure and death1. More than 1,500,000 persons with COVID-19 globally have died by December 20202, and treatment options are limited3. The COVID-19 pandemic has caused a hitherto unprecedented search for possible therapies, with almost 700 clinical trials initiated in the first quarter of 2020—and one in five of these trials target hydroxychloroquine (HCQ) or chloroquine (CQ)4. This remarkable attention was primarily due to in vitro data5, immunomodulatory capacities6, and the oral formulation and well-documented safety profiles. In March 2020, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization of HCQ7 and the number of prescriptions and usage outside clinical studies skyrocketed8. In many countries, HCQ or CQ were listed in treatment guidelines for COVID-19 (including,..