BackgroundBenefit of early awake prone positioning for COVID-19 patients hospitalised in medical wards and who need oxygen therapy remains to be demonstrated. The question was considered at the time of COVID-19 pandemic to avoid overloading the intensive care units. We aimed to determine whether prone position plus usual care could reduce the rate of non-invasive ventilation (NIV) or intubation or death as compared to usual care alone.MethodsIn this multicentre randomised clinical trial, 268 patients were randomly assigned to awake prone position plus usual care (N= 135) or usual care alone (N= 132). The primary outcome was the proportion of patients who underwent NIV or intubation or died within 28 days. Main secondary outcomes included the rates of NIV, of intubation or death, within 28 days.ResultsMedian time spent each day in the prone position within 72 h of randomisation was 90 min (IQR 30–133). The proportion of NIV or intubation or death within 28 days was 14.1% (19/135) in the prone position group and 12.9% (17/132) in the usual care group [odds ratio adjusted for stratification (aOR) 0.43; 95% confidence interval (CI) 0.14–1.35]. The probability of intubation, or intubation or death (secondary outcomes) was lower in the prone position group than in the usual care group (aOR 0.11; 95% CI 0.01–0.89 and aOR 0.09; 95% CI 0.01–0.76, respectively) in the whole study population and in the prespecified subgroup of patients with SpO2≥ 95% on inclusion (aOR 0.11; 95% CI 0.01–0.90, and aOR 0.09; 95% CI 0.03–0.27, respectively).ConclusionsAwake prone position plus usual care in COVID-19 patients in medical wards did not decrease the composite outcome of need for NIV or intubation or death.Trial registrationClinicalTrials.gov Identifier:NCT04363463. Registered 27 April 2020.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13054-023-04529-z.