BackgroundIn the few reports to date, the changes in superoxide dismutase (SOD), a key factor in cellular protection against superoxide, in COVID-19 have been very inconsistent and contradictory. There is also a lack of data on COVID-19 induced by Omicron variant. Further investigation is warranted to figure out SOD alterations in COVID-19, particularly within the context of ongoing Omicron variant infection, which may provide clues to its role within COVID-19 pathogenesis and open up new avenues for COVID-19 treatment.MethodsSOD activity in 109 COVID-19 patients (including 46 severe cases and 63 mild to moderate cases) and 30 matched healthy controls were quantified. Demographic data, blood cell counts, biochemical indicators, coagulation indicators, and inflammatory markers were also recorded.ResultsSOD, an important key node, experienced a significant decrease in COVID-19, with the severe patients exhibiting lower activity compared to the mild to moderate patients and control healthy. Notably, severe patients who deceased had the lowest SOD activity. Correlation analysis revealed significant correlations between SOD and inflammatory markers, organ injury markers, coagulation dysfunction indicators, nutritional markers, and lymphocytes counts. The ROC curve also showed good performance for the differentiation of severe cases and the prediction of death.ConclusionSOD activity was significantly decreased in COVID-19 infected with Omicron variant and significantly correlated with systemic changes, and could be used as a biomarker to assess disease severity and predict mortality in COVID-19 clinical pathway management. Additionally, this finding will contribute to exploring new potential direction for the treatment of severe COVID-19 patients.