Rationale: Previous studies investigating comorbidity impact on biologic effectiveness have been relatively small, of short duration, and have not compared biologic classes. Objectives: To determine the association between T2-related comorbidities and biologic effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data (n=21 countries, 2017-2022) to quantify pre- to post-biologic change for four outcomes (annual asthma exacerbation rate, % predicted FEV1 (ppFEV1), asthma control, and long-term oral corticosteroid daily dose [LTOCS]) in patients with/without allergic rhinitis (AR), chronic rhinosinusitis +/- nasal polyps (CRS+/-NP), NP, or eczema/atopic dermatitis (AD). Main results: Of 1765 patients, 1257, 421, and 87 initiated anti–IL-5/5R, anti-IgE, and anti–IL-4/13 therapies, respectively. In general, pre- to post-biologic improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS+/-NP experienced 23% (95% CI 10-35%, p<0.001) fewer exacerbations/year and had 59% (95% CI: 26-102%, p<0.001) higher odds of better post-biologic control than those without CRS+/-NP. Similar estimates were noted for those with comorbid NP (22% less exacerbations and 56% higher odds of better post-biologic control). Patients with SA and CRS+/-NP had an additional ppFEV1 improvement of 3.2% (95% CI: 1.0-5.3; p=0.004), a trend that was also noted in those with comorbid NP. The presence of AR or AD were not associated with pre- to post-biologic effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS+/-NP or NP may be considered a predictor of biologic effectiveness in patients with severe asthma.