COVID-19 is a newly discovered deadly disease with no proven definitive treatment until now . It is now proved that it can affect different body organs which necessitate intensive care management . Ozone (O3) therapy was used before for treating various viral infections like hepatitis B, human immune deficiency virus (HIV), and Ebola viruses . O3 also can manage hypoxia and increase tissue oxygenation, besides its anti-inflammatory and immunomodulatory properties which may have an important role in the management of cytokine storm . We used rectal O3 insufflation therapy assuming that it may have a beneficial role in the management of COVID-19 disease . Two sessions of rectal O3 therapy were given to a 60-year-old female patient who was confirmed COVID-19 positive . Before applying O3 therapy, she was hypoxic (sPO2:90 %) despite mechanical ventilation with high fraction inspired oxygen (FiO2:90 %). After therapy, she was markedly improved and discharged to the inpatient ward and then discharged home on day 10 post-admission . Another 40-year-old male patient who was confirmed COVID-19 positive and was home isolated received one session of O3 therapy . Before therapy, he was hypoxic (sPO2:85% on room air and 95% with O2 face mask 5 L/min). The patient showed gradual improvement over the next 3 days after therapy and becomes oxygen-independent (sPO2 became 94-97% on room air). No adverse effects were noticed in both cases . Rectal O3 insufflation can be used safely as adjuvant management for patients with COVID-19 disease.