Background: Selective immunoglobulin E deficiency (sIgED) is a rare immunological condition characterized by low serum IgE levels while maintaining normal levels of other immunoglobulin classes. Despite its underrecognized nature, sIgED has been implicated in immune dysregulation, potentially predisposing individuals to autoimmune and autoinflammatory diseases. Objective: This study aims to investigate the association between sIgED and immune-mediated diseases, exploring its prevalence, clinical implications, and underlying mechanisms. Methods: A retrospective cohort study was conducted over five years at a tertiary university hospital. Among 3,692 patients, individuals with serum IgE ≤ 2.5 kU/L were classified as having sIgED. Autoimmune and autoinflammatory conditions were analyzed in relation to IgE levels. Statistical analyses were performed using SPSS version 22.0. Results: Autoimmune and autoinflammatory diseases were significantly more prevalent in the sIgED group than in controls (25.2% vs. 15.6%, p < 0.001). Specific associations were observed with Hashimoto’s thyroiditis, familial Mediterranean fever, and Behçet’s disease. Mechanistically, sIgED appears to impair mucosal immune barriers and immune regulation, potentially contributing to disease pathogenesis. Conclusion: sIgED is associated with a higher prevalence of autoimmune and autoinflammatory diseases, emphasizing its potential role as a biomarker for immune dysregulation. These findings highlight the need for routine IgE level assessment in patients with suspected immune-mediated conditions and call for further research to elucidate underlying mechanisms.