Background: Although upregulated expression of local IgD has been reported in patients with chronic rhinosinusitis (CRS), its function is unclear. Objective: We sought to explore the expression and function of soluble IgD in patients with CRS, particularly CRS with nasal polyps. Methods: IgD levels in sinonasal mucosa were analyzed by using RT-PCR and ELISA. Numbers and phenotypes of IgD(+) cells were studied by means of immunohistochemistry, immunofluorescence, and flow cytometry. HMC-1 cells, a human mast cell line, and mast cells purified from eosinophilic polyps were cultured alone or with naive B cells purified from peripheral blood. The antigen specificity of nasal IgD was investigated by using ELISA. Results: The mRNA expression of immunoglobulin heavy constant delta gene, numbers of IgD(+) cells, and protein levels of secretory IgD in sinonasal mucosa were increased in patients with CRS with or without nasal polyps compared with control subjects. Numbers of IgD(+) plasmablasts were increased in both eosinophilic and noneosinophilic polyps, whereas numbers of IgD(+) mast cells were only increased in eosinophilic polyps. Cross-linking IgD induced serum preincubated HMC-1 cells and polyp mast cells to produce B-cell activating factor, IL-21, IL-4, and IL-13 and to promote IgM, IgG, IgA, and IgE production from B cells. In eosinophilic polyps expression of those B cell-stimulating factors in mast cells and close contact between mast cells and B cells were found. Moreover, positive correlations of total IgD levels with total IgE levels and eosinophilia and upregulation of specific IgD against house dust mites were discovered in eosinophilic polyps. Conclusion: IgD-activated mast cells can facilitate IgE production and eosinophilic inflammation in patients with CRS with nasal polyps.