Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS.Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.A total of 299 patients (mean [SD] age, 61  years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.ClinicalTrials.gov Identifier: NCT04327401.