Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) affects around 60% of patients with severe eosinophilic asthma (SEA). Benralizumab was recently approved for SEA add-on treatment. Objective: To assess the real-world effectiveness of benralizumab in SEA with or without CRSwNP. Methods: We conducted a multicenter observational study, including patients with SEA treated with benralizumab for 24 weeks in 12 Italian specialized facilities. Asthma exacerbations, Asthma Control Test (ACT), lung function, oral corticosteroid (OCS) dosage, and eosinophil and basophil count in peripheral blood were recorded at baseline and after 4, 12, and 24 weeks. The 22-item Sino-Nasal Outcome Test (SNOT-22) and Lund-Mackay scores were assessed at baseline and after 24 weeks in SEA+CRSwNP. Results: A total of 137 patients with late-onset SEA were included; 57.7% (79 of 137) showed the copresence of CRSwNP. Overall, severe asthma exacerbations decreased from 4 (3-6) to 0 (0-2) (P < .0001) after 24 weeks of treatment, and significant improvements were observed as early as 4 weeks in ACT score, OCS dosage, forced expiratory volume in the 1st second (FEV1)%, FEV1 (L), forced vital capacity (FVC)%, FEV1/FVC% (P < .0001), and forced expiratory flow between 25% and 75% of FVC (FEF25-75)% (P = .0022). Eosinophils and basophils in peripheral blood were rapidly depleted. In patients with SEA+CRSwNP, SNOT-22 decreased from 46 (39.5-64.5) to 32 (19-46) (P < .0001). Furthermore, in comparison with SEA, they showed enhanced responses with regard to ACT minimal clinically important difference (P = .0387), FEV1% (P = .017), FEV1 (L) (P = .02), and FEF25-75% (P = .0362). Conclusions: These real-world data suggest that benralizumab can represent a valid add-on therapeutic option for patients with SEA, especially with comorbid CRSwNP.