Aim In this study, we aimed to investigate the effectiveness of ozone therapy, which is one of the integrative medicine applications that has been used safely for many years, on the prevalence of mortality in patients receiving COVID-19 treatment. Methods This was a prospective, controlled study conducted on patients with COVID-19 who were hospitalized in Health Sciences University, Haydarpasa Numune Training and Research Hospital. In this study, 55 patients were included. The patients were divided into two groups as the ozone group and the control group. Ozone therapy (major autohemotherapy) was applied to 37 patients who were being treated with the appropriate COVID-19 treatment protocol determined by the infectious diseases committee of our hospital. The ozone treatment protocol consisted of seven sessions (1 session/day) of intravenous ozone administration, applied in a volume of 100 mL and a concentration of 30 μg/mL. Only the conventional COVID-19 treatment protocol was applied to 18 patients in the control group. Clinical follow-up was performed until the discharge of the patients from the hospital with successful treatment or until the mortality occurred. Factors affecting mortality were analyzed using univariate regression analysis. Results Intensive care unit (ICU) hospitalization was required in six of 37 patients who were treated with ozone (16.2%), while four of 18 patients in the control group required ICU treatment (22.2%) (p = 0.713). When the mortality rates between the two groups were compared, mortality was lower in the ozone group (p = 0.032). As a result of univariate logistic regression analysis performed to determine the factors affecting mortality, treatment without ozone therapy was determined as a risk factor for mortality (OR:0.149, 95%CI 0.026-0.863, p=0.034). Conclusion In this study, we demonstrated that administration of ozone therapy along with the conventional medical treatment in patients hospitalized for COVID-19 could reduce mortality.