question: OBJECTIVES: To evaluate the effects of inhaled epoprostenol and prone positioning, individually and in combination in mechanically ventilated patients with coronavirus disease 2019 and refractory hypoxemia. DESIGN: Retrospective study. SETTING: Academic hospital adult ICUs. PATIENTS: Adult patients who received inhaled epoprostenol and prone positioning during invasive ventilation were enrolled. Patients were excluded if inhaled epoprostenol was initiated: 1) at an outside hospital, 2) after prone positioning was terminated, 3) during extracorporeal membrane oxygenation or cardiopulmonary resuscitation, and 4) with Pao(2)/Fio(2) greater than 150 mm Hg. INTERVENTIONS: Inhaled epoprostenol and prone positioning. RESULTS: Of the 43 eligible patients, 22 and seven received prone positioning and inhaled epoprostenol alone, respectively, prior to their use in combination, Pao(2)/Fio(2) was not different pre- and post-prone positioning or inhaled epoprostenol individually (89.1 [30.6] vs 97.6 [30.2] mm Hg; p = 0.393) but improved after the combined use of inhaled epoprostenol and prone positioning (84.0 [25.6] vs 124.7 [62.7] mm Hg; p < 0.001). While inhaled epoprostenol and prone positioning were instituted simultaneously in 14 patients, Pao(2)/Fio(2) was significantly improved (78.9 [27.0] vs 150.2 [56.2] mm Hg, p = 0.005) with the combination. Twenty-seven patients (63%) had greater than 20% improvement in oxygenation with the combination of inhaled epoprostenol and prone positioning, and responders had lower mortality than nonresponders (52 vs 81%; p = 0.025). CONCLUSIONS: In critically ill, mechanically ventilated patients with coronavirus disease 2019 who had refractory hypoxemia, oxygenation improved to a greater extent with combined use of inhaled epoprostenol and prone positioning than with each treatment individually. A higher proportion of responders to combined inhaled epoprostenol and prone positioning survived compared with nonresponders. These findings need to be validated by randomized, prospective clinical trials.