Background: There is still no specific treatment strategies for COVID-19 other than supportive management. The potential biological benefits of ozonated autohemotherapy include reduced tissue hypoxia, decreased hypercoagulability, modulated immune function with inhibition of inflammatory mediators, improved phagocytic function, and impaired viral replication. Objective: To determine the impact of the use of ozonated blood on time to clinical improvement in patients with severe COVID-19 pneumonia. Design: A Quasi-Randomized Controlled Trial determined by admittance to the hospital based on bed availability. Setting: Internal Medicine ward at Policlinica Ibiza Hospital, Spain. Participants: Eighteen patients with COVID-19 infection (laboratory confirmed) severe pneumonia admitted to hospital between 20th March and 19th April 2020. The mean age of the cohort was 68 years-old and 72% (n=13) were male. Intervention: Patients admitted to the hospital during the study period were pre-randomized to different beds based on bed availability. Depending on the bed the patient was admitted, the treatment was ozone autohemotherapy or standard treatment. Patients in the therapy arm received ozonated blood twice daily starting on the day of admission for a median of four days. Each treatment involved administration of 200 mL autologous whole blood enriched with 200 mL of oxygen-ozone mixture with a 40 μg/mL ozone concentration. Main Outcomes: The primary outcome was time from hospital admission to clinical improvement, which was defined as either hospital discharge or a two-point improvement in clinical status measured on a six-point ordinal scale. Secondary outcomes were clinical improvement measured on the 7th, 14th and 28th day after admission, as well as time to a two-fold reduction in concentrations of C-reactive protein, ferritin, D-dimer and lactate dehydrogenase. Results: Nine patients (50%) received ozonated autohemotherapy beginning on the day of admission. Ozonated autohemotherapy was associated with shorter time to clinical improvement (median [IQR]), 7 days [6-10] vs 28 days [8-31], p=0.04) and better outcomes at 14-days (88.8% vs 33.3%, p=0.01). In risk-adjusted analyses, ozonated autohemotherapy was associated with a shorter mean time to clinical improvement (-11.3 days, p=0.04, 95% CI -22.25 to -0.42). Conclusion: Ozonated autohemotherapy was associated with a significantly shorter time to clinical improvement in this quasi-randomized controlled trial. Given the small sample size and study design, these results require evaluation in larger randomized controlled trials.