Importance Aside from supportive management, there remains no specific treatment for Coronavirus Disease 2019 (COVID-19). Objective: Determine whether ozonated autohemotherapy is associated with a shorter time to clinical improvement in patients with severe COVID-19 pneumonia. Design: Single-center proof-of-concept prospective cohort study. Setting: Internal Medicine ward at Policlinica Ibiza Hospital, Spain. Participants: Eighteen consecutive patients with laboratory confirmed COVID-19 infection and severe pneumonia who were admitted to hospital between 20th March and 19th April 2020. Exposures: Patients in the ozonated autohemotherapy arm received hemotherapy twice daily starting on the day of admission for a median of 4 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. Patients in the control arm received supportive care. Assignment to hemotherapy versus usual care was determined based on the admitting physician on the day of admission, with only one of the three possible physicians prescribing ozonated autohemotherapy 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 2-fold reduction in concentrations of C-protein reactive, ferritin, D-dimer and lactate dehydrogenase. Results: The mean age of the cohort was 68 y and 72% (n=13) were male. Nine patients (50%) received ozonated autohemotherapy beginning on the day of admission. In unadjusted comparisons, ozonated autohemotherapy was associated with significantly shorter time to clinical improvement (median [IQR]), 7 days [6-10] vs 28 days [8-31], p=0.04) and significantly higher proportion of patients achieving 14-day clinical improvement (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). Conclusions and Relevance: Ozonated autohemotherapy was associated with a significantly shorter time to clinical improvement in this prospective cohort study. Given the small sample size and single-center study design, these observations require evaluation in larger randomized controlled trials.