<p>STAT3 hyper-IgE syndrome (STAT3-HIES), historically known as Job syndrome, is a rare primary immunodeficiency caused by dominant-negative mutations in STAT3. STAT3-HIES is characterized by impaired mucosal immunity, connective tissue abnormalities, and recurrent cutaneous and pulmonary infections. Although STAT3-dependent immune and epithelial pathways are central to airway host defense, the respiratory microbiome in STAT3-HIES remains poorly defined. To address this question, we profiled upper and lower respiratory tract microbiomes using 16S rDNA gene sequencing of oral rinse samples from eight STAT3-HIES participants and eight matched healthy controls, and bronchoalveolar lavage fluid (BALF) samples from eight STAT3-HIES participants and six healthy controls that passed sequencing quality thresholds. Oral rinse samples from STAT3-HIES participants showed lower phylogenetic diversity and significantly altered microbial community structure compared with controls. In BALF, α-diversity was comparable between groups, but β-diversity differed significantly, indicating altered lower airway microbial community composition in STAT3-HIES. Differential abundance analysis identified enrichment of the genus Rothia in STAT3-HIES BALF, and Rothia relative abundance positively correlated with BALF IL-1β, IL-1RA, and IL-8. Although limited by cohort size, these findings provide the first characterization of respiratory microbiome alterations in STAT3-HIES and suggest that impaired STAT3-dependent immune pathways may influence airway microbial ecology and inflammatory responses.</p>