The emergence of the Pandemic COVID-19, with a fatal outcome in a large proportion of cases, created the need for development of therapeutic protocols and identification of effective treatment methods. Supportive measures remain the cornerstone for treating COVID-19 in the absence of specific therapies. Ozone may exert its antiviral actions and ozone therapy has been demonstrated therapeutical usefulness in influenza and novel viruses. Ozone therapy consists in the administration of a mixture of ozone and oxygen, called medical ozone, which has been used for over a century as an unconventional medicine practice for several diseases. Medical ozone rationale in COVID-19 relies in the possibility of contrasting endothelial dysfunction, modulating the immune response and acting as a virustatic agent. So far, no prospective controlled study was performed on studying the influence of major haemozonetherapy on COVID19 patients in ICU settings. We performed prospective, controlled, randomized study on 100 patients with COVID19 admitted to ICU divided in 2 groups: LO - ozone therapy LC-control. Major outcomes (mortality) and secondary outcomes (Length of stay, NIV duration, MV duration, inflammatory, oxygenation profile) were compared. No statistical difference was observed between ozone therapy and control group with regards to primary outcome of the treatment, even if absolute numbers indicate rate of mortality 34% in LC vs 26% in LO group. As well no difference in duration of length of stay, duration of NIV, MV was observed between two groups.