| Summary: | <i>Background:</i> High total IgE levels are weak predictors of T2<sub>High</sub> and have been reported in nonallergic asthma. Therefore, the role of total serum IgE (IgE) in the T2<sub>High</sub> phenotype is still debated. Objective: This study investigated the reliability of stratifying asthmatics into IgE<sub>High</sub> and IgE<sub>Low</sub> within the T2<sub>High</sub> and T2<sub>Low</sub> phenotypes. <i>Methods:</i> This cross-sectional single-center study investigated the association of clinical, functional, and bio-humoral parameters in a large asthmatic population stratified by IgE ≥ 100 kU/L, allergen sensitization, B-EOS ≥ 300/µL, and F<sub>E</sub>NO ≥ 30 ppb. <i>Results:</i> Combining T2 biomarkers and IgE identifies (1) T2<sub>Low</sub>-IgE<sub>Low</sub> (15.5%); (2) T2<sub>Low</sub>-IgE<sub>High</sub> (5.1%); (3) T2<sub>High</sub>-IgE<sub>Low</sub> (33.6%); and T2<sub>High</sub>-IgE<sub>High</sub> (45.7%). T2<sub>Low</sub>-IgE<sub>Low</sub> patients have more frequent cardiovascular and metabolic comorbidities, a higher prevalence of emphysema, and higher LAMA use than the two T2<sub>High</sub> subgroups. Higher exacerbation rates, rhinitis, and anxiety/depression syndrome characterize the T2<sub>Low</sub>-IgE<sub>High</sub> phenotype vs. the T2<sub>Low</sub>-IgE<sub>Low</sub> phenotype. Within the T2<sub>High</sub>, low IgE was associated with female sex, obesity, and anxiety/depression. <i>Conclusions:</i> High IgE in T2<sub>Low</sub> patients is associated with a peculiar clinical phenotype, similar to T2<sub>High</sub> in terms of disease severity and nasal comorbidities, while retaining the T2<sub>Low</sub> features. IgE may represent an additional biomarker for clustering asthma in both T2<sub>High</sub> and T2<sub>Low</sub> phenotypes rather than a predictor of T2<sub>High</sub> asthma “<i>per se</i>”.
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