Objective To analyze the changes in serum immunoglobulin E （IgE）， interleukin-6 （IL-6）， high-mobility group protein B1 （HMGB1）， β2-microglobulin （β2-M）， and T lymphocyte subsets in patients with secretory otitis media （SOM） and to evaluate their clinical significance. Methods A total of 185 patients with SOM admitted to Wuhan First Hospital between March 2023 and March 2025 were enrolled as the patient group， and 185 healthy individuals who underwent routine physical examinations at our hospital during the same period served as the control group. Serum levels of IgE， IL-6， HMGB1， and β2-microglobulin（β2-M）， as well as peripheral blood T lymphocyte subsets， were compared between the two groups. Based on disease duration， the patients were further classified into acute （n = 43）， subacute （n = 61）， and chronic （n = 81） subgroups. Levels of the serum markers and T lymphocyte subsets were compared across these three subgroups. The diagnostic value of the serum markers for SOM was evaluated， and their correlations with peripheral blood T lymphocyte subsets were analyzed. Results he levels of serum IgE， IL-6， HMGB1， β2-M， and peripheral blood CD8⁺ were significantly higher in the disease group than in the control group， whereas the levels of peripheral blood CD4⁺ and CD4⁺/CD8⁺ were significantly lower （P < 0.05）. Across the acute， subacute， and chronic subgroups， the levels of serum IgE， IL-6， HMGB1， β2-M， and CD8⁺ exhibited a progressive increasing trend， while CD4⁺ and CD4⁺/CD8⁺ levels showed a corresponding decreasing trend （P < 0.05）. The combined measurement of serum IgE， IL-6， HMGB1， and β2-M yielded a higher area under the curve （AUC） for diagnosing SOM compared to each marker alone （P < 0.05）， with a sensitivity of 88.65% and specificity of 76.76%. Furthermore， serum levels of IgE， IL-6， HMGB1， and β2-M were positively correlated with peripheral blood CD8⁺ levels （r = 0.618， 0.578， 0.622， 0.549； P < 0.05）， and negatively correlated with CD4⁺ and CD4⁺/CD8⁺ ratios （r = -0.539， -0.573， -0.519， -0.559 for CD4⁺； r = -0.604， -0.618， -0.559， -0.649 for CD4⁺/CD8⁺； P < 0.05）. Conclusion The progression of SOM is associated with alterations in serum markers and peripheral blood T lymphocyte subsets. Furthermore， the combination of serum IgE， IL-6， HMGB1， and β2-MG demonstrates enhanced diagnostic value in patients with SOM， and a significant correlation exists between these four markers and the levels of peripheral blood T lymphocyte subsets.