Background: There is no pharmacological intervention on the treatment of hypoxemia and respiratory distress in COVID-19 patients. Objective: The objective of the study was to study the effect of the reduced form of methylene blue (MB) on the improvement of oxygen saturation (SpO 2 ) and respiratory rate (RR). Methods: In an academic medical center, 80 hospitalized patients with severe COVID-19 were randomly assigned to receive either oral MB along with standard of care (SOC) (MB group, n = 40) or SOC only (SOC group, n=40). The primary outcomes were SpO 2 and RR on the 3 rd and 5 th days. The secondary outcomes were hospital stay and mortality within 28 days. Results: In the MB group, a significant improvement in SpO 2 and RR was observed on the 3 rd day (for both, p < 0.0001) and also the 5 th day (for both, p < 0.0001). In the SOC group, there was no significant improvement in SpO 2 (p = 0.24) and RR (p = 0.20) on the 3 rd day, although there was a significant improvement of SpO 2 (p = 0.002) and RR (p = 0.01) on the 5 th day. In the MB group in comparison to the SOC group, the rate ratio of increased SpO 2 was 13.5 and 2.1 times on the 3 rd and 5 th days, respectively. In the MB group compared with the SOC group, the rate ratio of RR improvement was 10.1 and 3.7 times on the 3 rd and 5 th days, respectively. The hospital stay was significantly shortened in the MB group (p = 0.004), and the mortality was 12.5% and 22.5% in the MB and SOC groups, respectively. Conclusions:The addition of MB to the treatment protocols significantly improved SpO 2 and respiratory distress in COVID-19 patients, which resulted in decreased hospital stay and mortality. ClinicalTrials.gov: NCT04370288 (REV INVEST CLIN. 2021;73(3):XX-XX)

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