The aim of this study was to evaluate the impact of hyperbaric oxygen therapy (HBOT) on patients with SARS-CoV-2 infection and determine its efficacy and safety in reducing treatment failure events.A retrospective cohort study involving patients with COVID-19 was conducted. Inverse probability of treatment weighting (IPTW) was used to balance covariates between the HBOT and non-HBOT groups. The primary endpoint was the occurrence of a clinical treatment failure event, defined as all-cause mortality, abandonment of treatment, or transfer to the Intensive Care Unit due to worsening condition.A total of 720 patients with COVID-19 were enrolled in the study, with 27 patients receiving HBOT and 693 patients not receiving HBOT. The occurrence of treatment failure was significantly lower in the HBOT group compared to the non-HBOT group, with no treatment failure events in the HBOT group versus 36 events in the non-HBOT group. The IPTW database analysis results showed that in comparison to the non-HBOT group, the hazard ratio (HR) for treatment failure in the HBOT group was less than 0.001 (95% CI: <0.001 ~ <0.001, p<0.001). Lymphocyte count >0.8×109/L and HBOT was associated with a significantly lower risk of treatment failure. Glucocorticoid use was associated with a higher risk of treatment failure. The incidence of venous thrombosis events was significantly higher in the HBOT group compared to the non-HBOT group.This study revealed that adjunctive HBOT significantly reduces the risk of treatment failure in patients with COVID-19 and is associated with satisfactory safety. HBOT shows promise as a beneficial therapy for improving outcomes in COVID-19-infected patients.© 2024 Wang et al.