Background/Objective: Sensitization to specific IgE Staphylococcus aureus enterotoxins (SEs) is associated with an increased risk for severe asthma development. Limited data exist regarding the association of seropositivity for specific IgE SEs and the different aspects of severe asthma. We aimed to determine whether the presence of SEs is associated with asthma-related parameters such as inflammatory cells in the airways, features of airway remodeling, and other variables relating to asthma assessment and severity. Methods: Fifty patients with severe asthma were recruited in the study. Demographics, comorbidities, asthma duration, and asthma medication were recorded by treating physicians. Specific IgE SE measurement, lung function, atopic status, asthma control test (ACT), sputum induction, bronchoscopy with BAL, and indices of airway remodeling were also assessed. Results: Twelve patients were positive to enterotoxin sensitization. Patients seropositive to specific IgE SEs significantly differed in regard to FEV₁% pred and FEV₁/FVC ratio compared to seronegative ones. Analyzing the inflammatory variables obtained from induced sputum, BAL, and endobronchial biopsies, the only significant difference was that of smooth muscle area (SMA), which was greater in specific IgE SE seropositive patients. The multivariate linear regression analysis showed two significant associations of specific IgE SE seropositivity. We found a negative with FEV₁% pred with beta standardized coefficient 95%CI −0.054 (−0.083, −0.031), p < 0.001, and a positive with SMA with beta standardized coefficient 95%CI 0.054 (0.081, 0.037), p < 0.001. Conclusions: Seropositivity to specific IgE SEs in severe asthma is associated with more severe airflow limitation, obstruction, and upregulation in SMA, indicating a possible role in the remodeling process.