Background: Immunoglobulin (Ig) E-mediated pathophysiological mechanisms are common in allergic diseases including severe allergic asthma (SAA). The anti-IgE monoclonal antibody omalizumab may be particularly beneficial for patients with SAA and multiple allergic comorbidities (AC) including perennial/seasonal rhinitis, conjunctivitis, atopic dermatitis (AD), and food allergy. Methods: We conducted a post-hoc analysis of the patients from the STELLAIR study (n=872, 149 minors and 723 adults). The patients were classified based on the presence of multiple AC (≥ 3 AC or < 3 AC) or AD as assessed by questionnaire. Response to omalizumab was assessed after 4– 6 months (T4– 6) and after 12 months (T12). Asthma response at T4– 6 was based on global evaluation of treatment effectiveness, reduction of ≥ 40% in annual exacerbation rate, and a combination of both. Asthma response at T12 was based on change in yearly exacerbation and hospitalization rates. AC improvement at T12 was based on patient perception. Results: Patients with ≥ 3 AC demonstrated a higher combined response to omalizumab (74.7% vs 58.3%) at T4– 6 and had reduced yearly exacerbation and hospitalization rates (88.9% vs 77.4% and − 94.0% vs − 70.5%, respectively). Patients with ≥ 3 AC were more likely to show an improvement in their AC (85.3% vs 51.9%) at T12. Results were similar in minors and adults. The presence of AD was associated with greater omalizumab effectiveness at T4– 6 and a greater AC improvement at T12. Improvement of AD and food allergies at T12 were 73.2% and 38.7%, respectively, in the population overall. Conclusion: This post-hoc analysis of the STELLAIR study shows that omalizumab is beneficial for all SAA patients and especially for patients with multiple AC or AD. In patients with ≥ 3 AC, omalizumab also improved AC outcomes.