The objective: to evaluate the effectiveness of inhaled surfactant therapy in the integrated treatment of severe COVID-19 pneumonia in a multicenter prospective clinical trial of surfactant-BL. Subjects and methods. 122 patients with severe COVID-19-associated pneumonia treated in two treatment centers were enrolled in the study. All of them received antiviral, anticoagulant and anti-inflammatory therapy. 56 patients also received inhalation therapy with surfactant-BL (OOO Biosurf, St. Petersburg, Russia) at a dose of 1 mg/kg 2-3 times a day. The remaining 66 patients received no surfactant-BL inhalation. When included into the study, all patients were divided into two groups based on severity of the condition at the time of inclusion: 62 people (Group I) needed oxygen inhalation through a face mask with the flow of 6-8 L/min for hypoxemia correction (27 received surfactant therapy and 35 did not); other 60 patients (Group II) required non-invasive respiratory support (constant positive airway pressure, non-invasive mechanical ventilation, high-flow oxygen therapy), of them 29 received surfactant therapy, while 31 patients did not. Results. In Group I, switching to invasive mechanical ventilation was required for 3/27 (11.1%) patients who received surfactant therapy, and 10/35 (28.6%) who received no surfactant therapy (p = 0.085); lethality made 3/27 (11.1%) and 9/35 (25.7%) (p = 0.131), respectively. In Group II, among those who received surfactant therapy, 5/29 (17.2%) were switched to invasive mechanical ventilation and 18/31 (58.1%) among those who did not receive it (p = 0.001); lethality made 5/29 (17.2%) and 18/31 (58.1%) (p = 0.001), respectively. In the pooled group of 122 patients with severe COVID-19-associated pneumonia, 8 (14.3%) of 56 patients who received surfactant died, and 27 (40.9%) of 66 died among those who did not receive it, (p = 0.001). Conclusion: Inhalation surfactant therapy can reduce the frequency of switching patients to mechanical ventilation and statistically significantly reduce lethality caused by severe pneumonia associated with SARS-CoV-2. © 2020 New Terra Publishing House. All rights reserved.