Airway pressure release ventilation is a ventilatory mode characterized by a mandatory inverse inspiratory:expiratory ratio with a very short expiratory phase, aimed to avoid derecruitment and allow spontaneous breathing. Recent basic and clinical evidence suggests that this mode could be associated with improved outcomes in patients with acute respiratory distress syndrome. The aim of this study was to compare the outcomes between airway pressure release ventilation and traditional ventilation targeting low tidal volume, in patients with severe coronavirus disease 2019. Single-center randomized controlled trial. ICU of a Mexican referral center dedicated to care of patients with confirmed diagnosis of coronavirus disease 2019. Ninety adult intubated patients with acute respiratory distress syndrome associated with severe coronavirus disease 2019. Within 48 hours after intubation, patients were randomized to either receive ventilatory management with airway pressure release ventilation or continue low tidal volume ventilation. Forty-five patients in airway pressure release ventilation group and 45 in the low tidal volume group were included. Ventilator-free days were 3.7 (0-15) and 5.2 (0-19) in the airway pressure release ventilation and low tidal volume groups, respectively (p = 0.28). During the first 7 days, patients in airway pressure release ventilation had a higher Pao2/Fio2 (mean difference, 26 95%CI, 13-38; p < 0.001) and static compliance (mean difference, 3.7 mL/cm H2O 95% CI, 0.2-7.2; p = 0.03), higher mean airway pressure (mean difference, 3.1 cm H2O 95% CI, 2.1-4.1; p < 0.001), and higher tidal volume (mean difference, 0.76 mL/kg/predicted body weight 95% CI, 0.5-1.0; p < 0.001). More patients in airway pressure release ventilation had transient severe hypercapnia, defined as an elevation of Pco2 at greater than or equal to 55 along with a pH less than 7.15 (42% vs 15%; p = 0.009); other outcomes were similar. Overall mortality was 69%, with no difference between the groups (78% in airway pressure release ventilation vs 60% in low tidal volume; p = 0.07). In conclusion, when compared with low tidal volume, airway pressure release ventilation was not associated with more ventilator-free days or improvement in other relevant outcomes in patients with severe coronavirus disease 2019.