In severe COVID-19 pulmonary failure, hypoxia is mainly related to pulmonary vasodilation with altered hypoxic pulmonary vasoconstriction (HPV). Besides prone positioning, other non-ventilatory strategies may reduce the intrapulmonary shunt. This study has investigated almitrine, a pharmacological option to improve oxygenation. Patients and Method. A case control series of 17 confirmed COVID-19 mechanically ventilated patients in prone or supine positioning was collected: 10 patients received two doses of almitrine (4 and 12 mcg/kg/min) at 30-45 min interval each, and were compared to 7 control COVID-matched patients conventionally treated. The end-point was the reduction of intra-pulmonary shunt increasing the PaO2 and ScvO2. Results Patients were male (59%) with median (25th, 75th percentiles) age of 70 (54-78) years and a BMI of 29 (23-34). At stable mechanical ventilatory settings, PaO2 (mmHg) at FiO2 1 (135 (85, 195) to 214 (121, 275); p = 0.06) tended to increase with almitrine. This difference was significant when the best PaO2 between the 2 doses was used : 215 (123,294) vs baseline (p = 0.01). A concomitant increase in ScvO2 occurred ((73 (72, 76) to 82 (80, 87); p = 0.02). Eight over 10 almitrine-treated patients increased their PaO2, with no clear dose-effect. During the same time, the controls did not change PaO2. In conclusion, in early COVID-19 with severe hypoxemia, almitrine infusion is associated with improved oxygenation in prone or supine positioning. This pharmacological intervention may offer an alternative and/or an additional effect to proning and might delay or avoid more demanding modalities such as ECMO.