Abstract Importance Hypoxemia in COVID-19 pneumonia is dispositive for hospitalization and mechanical ventilation and contributes to mortality. Other than oxygen supplementation, there is no treatment that resolves hypoxemia in COVID-19 pneumonia. Objective COVID-19 pneumonia sustains a massive increase in lipid mediators, especially thromboxane A2 >> PGE2 > PGD2. Thromboxane A2 induces pulmonary venoconstriction, increases pulmonary capillary pressure and contributes to pulmonary edema. High thromboxane A2 metabolite levels are strongly associated with respiratory failure and mortality in hospitalized COVID-19 patients. Ramatroban (Baynas®, Bayer Yakuhin Ltd., Japan) is an inexpensive, orally bioavailable, thromboxane A2 receptor antagonist. Ramatroban was administered to patients with COVID-19 pneumonia and hypoxemia to explore the effect of thromboxane A2 antagonism on clinical symptoms and outcomes. Design, Setting, and Participants A retrospective case series comprising 4 consecutive outpatients, 22 to 87 years of age, with COVID-19 pneumonia and hypoxemia treated with ramatroban between April and July 2021 in India. Main Outcomes and Measures The primary outcome measure was blood oxygen saturation using pulse oximetry (SpO2). Secondary outcome measures were respiratory distress and need for hospitalization. Results Four COVID-19 outpatients had developed progressive respiratory distress and hypoxemia. Within 12-36 hours of the first dose of ramatroban, all four patients experienced increase in SpO2 and decrease in respiratory distress, which obviated hospitalization. Continued treatment for 5 days was associated with complete resolution of respiratory distress and hypoxemia. Conclusions and Relevance There is an unmet medical need for drugs that target the hemodynamic, prothrombotic, and maladaptive immune responses that lead to pneumonia and respiratory failure following SARS-CoV-2 infection. As an anti-vasospastic, broncho-relaxant, anti-thrombotic and immunomodulatory agent, ramatroban addresses the fundamental host response mechanisms underlying respiratory and critical organ failure in COVID-19. Ramatroban merits study in randomized clinical trials that might offer hope for a cost-effective pandemic treatment.