Effectiveness and Safety of Ozone Therapy in Humans: An Umbrella Review of Systematic Reviews with Meta-Analyses of Randomized Clinical Trials

Background/Objectives: Ozone therapy has been proposed across multiple clinical conditions based on hormetic, antioxidant, and immunomodulatory effects, but its efficacy and safety remain controversial. We conducted an umbrella review to appraise the effectiveness and safety of ozone therapy using evidence from meta-analyses of randomized controlled trials (RCTs). Methods: We searched MEDLINE, Web of Science, Embase, and the Cochrane Library from inception to 14 February 2025, with an updated search performed on 9 May 2026. Eligible studies were systematic reviews with meta-analyses comparing ozone therapy with non-active controls, including placebo, sham, saline, or standard care. Methodological quality was evaluated with AMSTAR-2 and certainty of evidence with GRADE. Results: Of 1243 records identified, seven meta-analyses representing four clinical indications (chronic periodontitis, COVID-19, diabetic foot ulcers, and impacted mandibular third-molar surgery) were included. In chronic periodontitis, evidence was mixed: one meta-analysis found no significant adjunctive benefit, whereas a more recent meta-analysis reported improvements in probing depth and gingival index, but not in bleeding on probing, plaque index, or clinical attachment level. For COVID-19, ozone therapy reduced PCR positivity at follow-up (RR 0.07; 95% CI 0.01–0.34), although this was considered a clinically non-important surrogate endpoint, and showed no significant benefit for hospital stay, intensive care unit admission, or mortality. For diabetic foot ulcers, ozone therapy was not superior to control treatment for ulcer healing (RR 1.69; 95% CI 0.90–3.17) or reduction in ulcer area. In third-molar surgery, ozone therapy did not reduce swelling or improve mouth opening, but was associated with improved short-term quality of life and reduced analgesic use. Safety outcomes were inconsistently reported, and available data did not allow firm conclusions regarding adverse events. The certainty of evidence was low or very low for all outcomes. Conclusions: Despite mechanistic plausibility, current meta-analytic evidence from RCTs remains inconsistent, methodologically fragile, and largely based on low- or very low-certainty findings. Routine clinical use is not justified pending adequately powered, blinded RCTs with standardized dosing and delivery, patient-centered endpoints, and rigorous safety monitoring.