The evaluation of new therapeutic resources against coronavirus disease 2019(COVID‐19) represents a priority in clinical research considering the minimal options currently available. To evaluate the adjuvant use of systemic oxygen‐ozone administration in the early control of disease progression in patients with COVID‐19pneumonia. PROBIOZOVID is an ongoing, interventional, randomized, prospective, and double‐arm trial enrolling patients with COVID‐19 pneumonia. From a total of 85patients screened, 28 were recruited. Patients were randomly divided into ozone‐autohemotherapy group (14) and control group (14). The procedure consisted of a daily double‐treatment with systemic Oxygen–ozone administration for 7 days. All patients were treated with ad interim best available therapy. The primary outcome was delta in the number of patients requiring orotracheal‐intubation despite treatment. Secondary outcome was the difference of mortality between the two groups. Moreover, hematological parameters were compared before and after treatment. No differences in the characteristics between groups were observed at baseline. As a preliminary report, we have observed that one patient for each group needed intubation and was transferred to ITU. No deaths were observed at 7–14 days of follow-up. Thirty‐day mortality was 8.3% for ozone group and 10% for controls. Ozonetherapy did not significantly influence inflammation markers, hematology profile, and lymphocyte subpopulations of patients treated. Ozone therapy had an impact on the need for ventilatory support, although did not reach statistical significance. Finally, no adverse events related to the use of ozone‐autohemotherapy were reported. Preliminary results, although not showing statistically significant benefits of ozone on COVID‐19, did not report any toxicity.