BACKGROUND Pneumonia caused by coronavirus originated in Wuhan, China in late 2019 and has spread around the world, becoming a pandemic. Many patients deteriorate rapidly and require intubation and mechanical ventilation, which is causing the collapse of healthcare systems in many countries. Coronavirus infection is associated with extensive lung inflammation and microvascular thrombosis, which can result in hypoxia. It can also cause severe and lasting harm in other organs, including the heart and kidneys. At present, there is no proven and efficacious treatment for this new disease. Consequently, there is a growing tendency to use novel methods. Ozone therapy consists of administration of a mixture of oxygen and ozone (a molecule consisting of 3 oxygen atoms). The potential benefits of this therapy include reduced tissue hypoxia, decreased hypercoagulability, renal and heart protection, modulated immune function, improved phagocytic function, and impaired viral replication. CASE REPORT We report rapidly improved hypoxia with associated decreases in inflammatory markers and D-dimer immediately after 1-4 sessions of oxygen-ozone (O(2)-O(3)) therapy in 3 patients with COVID-19 pneumonia who presented with respiratory failure. Invasive mechanical ventilation was not required in these 3 patients. All patients were discharged home on days 3-4 after O(2)-O(3) therapy. CONCLUSIONS O(2)-O(3) therapy appears to be an effective therapy for COVID-19 patients with severe respiratory failure. Large controlled clinical trials are required to study the efficacy and safety of using O(2)-O(3) therapy compared with the standard supportive case in patients with COVID-19 in terms of the need for invasive ventilation and length of hospital and intensive care unit stays.