<jats:title>SUMMARY</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We evaluated the efficacy and safety of azithromycin in hospitalised patients with COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In this randomised, controlled, open-label, adaptive platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge (or one of the other treatment arms). Patients were twice as likely to be randomised to usual care as to any of the active treatment groups. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://clinicaltrials.gov">clinicaltrials.gov</jats:ext-link> (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04381936">NCT04381936</jats:ext-link>).</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Between 7 April and 27 November 2020, 2582 patients were randomly allocated to receive azithromycin and 5182 patients to receive usual care alone. Overall, 496 (19%) patients allocated to azithromycin and 997 (19%) patients allocated to usual care died within 28 days (rate ratio 1·00; 95% confidence interval [CI] 0·90-1·12; p=0·99). Consistent results were seen in all pre-specified subgroups of patients. There was no difference in duration of hospitalisation (median 12 days vs. 13 days) or the proportion of patients discharged from hospital alive within 28 days (60% vs. 59%; rate ratio 1·03; 95% CI 0·97-1·10; p=0·29). Among those not on invasive mechanical ventilation at baseline, there was no difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0·97; 95% CI 0·89-1·07; p=0·54).</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>In patients hospitalised with COVID-19, azithromycin did not provide any clinical benefit. Azithromycin use in patients hospitalised with COVID-19 should be restricted to patients where there is a clear antimicrobial indication.</jats:p></jats:sec><jats:sec><jats:title>Funding</jats:title><jats:p>UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).</jats:p></jats:sec>