Staphylococcus aureus (S. aureus) secreting staphylococcal enterotoxins (SEs) plays a pathogenic role in severe asthma. It is not known whether omalizumab is effective in reducing SE-IgE-mediated airway inflammatory responses in patients with either atopic or non-atopic severe asthma. We conducted a prospective observational study to assess the clinical efficacy of omalizumab therapy in severe allergic and non-allergic asthmatics with SE-IgE positivity. Bronchial biopsy tissues and pro-inflammatory cell profiles in the induced sputum were obtained before a 12-week course of omalizumab to evaluate the clinical associations. Among 90 severe asthmatics with high serum IgE, around 28% of allergic severe asthmatics had SE-IgE, while more than 60% of non-allergic severe asthmatics had serum SE-IgE. Omalizumab effectively improved asthma control in severe asthmatics with SE-IgE, but to a less extent than ones without SE-IgE. Either allergic or non-allergic asthmatics with SE-IgE had higher expression of IL-8 mRNA in their bronchial tissues, associated with an increase in airway neutrophil counts. This neutrophilic inflammation was refractory to omalizumab treatment and contributed to 60% of allergic and 80% of non-allergic severe asthmatics with SE-IgE having sub-optimal control of asthma with omalizumab. Add-on clarithromycin therapy improved the sub-optimally controlled SE-IgE positive asthmatics. Presence of SE-IgE in severe asthmatics may increase IL-8-mediated airway neutrophilia and attenuate the clinical efficacy of omalizumab. Assessing serum SE-IgEs is important for assessing the clinical efficacy of omalizumab in allergic or non-allergic severe asthmatics.