Locally increased IgE levels plays a pathological role in chronic rhinosinusitis with nasal polyps (CRSwNP).This study aimed to investigate whether S. aureus could induce aberrant IgE synthesis in CRSwNP and the potential mechanisms involved.Total IgE, IL-4, IL-5, and IL-13 concentrations in the supernatants of the cultures stimulated with S. aureus lysate were assessed by ELISA. S. aureus-induced cellular responses were investigated by single-cell RNA-sequencing (scRNA-seq). Flow cytometry and RT-PCR were employed to analyze B-cell subsets and stimulated cell ε-germline transcript (ε-GLT) expression, respectively. IgE+ B cell and the germinal center (GC) localization were assessed by immunohistochemistry and immunofluorescence.S. aureus lysate induced IgE production in the supernatants of nasal polyp (NP) tissues but not in those of healthy nasal mucosa. Moreover, IgE levels increased from days 2 to 4 post-stimulation, paralleling the enhanced ε-GLT, IL-5 and IL-13 expression. ScRNA-seq revealed that there were increased IL-5 and IL-13 in group 2 innate lymphoid cells (ILC2s) and identified a clonal overlap between unstimulated memory B cells and S. aureus-stimulated plasma cells. The enriched IgE within NPs was mainly produced by IgE-negative memory B cells. Cellular evidence indicated that the IgE memory response to S. aureus might also exist in the peripheral blood of CRSwNP patients. The S. aureus-induced IgE memory response was associated with elevated IgE levels in NPs, asthma, and postoperative CRSwNP recurrence.S. aureus induced an IgE response via IgE-negative memory B cells in CRSwNP patients, possibly contributing to CRSwNP development.Copyright © 2023. Published by Elsevier Inc.