A great deal of evidence has accumulated suggesting an important role of mucosal immunity not only in preventing COVID-19 but also in the pathogenesis of this infection. The aim of the study was to evaluate the levels of secretory immunoglobulin A (sIgA) in different compartments of the upper respiratory tract in COVID-19 patients in relation to the severity of the disease and treatment with a bacteria-based immunomodulating agent (Immunovac VP4). The titers of sIgA were determined by ELISA in nasal epithelial swabs, pharyngeal swabs, and salivary gland secretions at baseline and on days 14 and 30 of treatment. The levels of nasal, pharyngeal and salivary sIgA were significantly lower in more severe patients (subgroup A) than in less severe patients (subgroup B), p <
0.01. In subgroup A, the patients who received Immunovac VP4 had higher pharyngeal sIgA levels in convalescent period than those who did not receive the therapy p <
0.05. In subgroup B patients, an increase in immunoglobulin levels was observed from baseline to day 14 of treatment whether they received the add-on therapy or not, p <
0.01. On day 30 of treatment, the sIgA levels in the standard treatment group, however, decreased, while the patients receiving the immunomodulating agent maintained high sIgA levels, p <
0.05. Oxygen saturation significantly increased by day 14 in both groups, p <
0.001. However, it was higher in the Immunovac VP4 group than in the standard treatment group, p <
0.01. Thus, addition of a bacterial lysate-based immunomodulating agent to the treatment regimen for moderate-to-severe COVID-19 induces the production of pharyngeal and salivary sIgA. SIgA production is inversely correlated to CRP levels and percentage of lung involvement on CT scan and is directly correlated to SpO