Background: Within the last years, monoclonal antibodies (biologicals) have revolutionized the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and significantly improved symptom control in otherwise refractory cases. The effectiveness of the biological mepolizumab, an IL-5 receptor antibody, has not yet been investigated extensively. This multi-centric study assesses its impact on a large German patient cohort including biological naïve and switched patients. Methodology: In this retrospective multi-centric study, patients with the diagnosis of severe CRSwNP treated with mepolizumab by German tertiary referral centers were included. Data were collected retrospectively from patient records. The change from baseline regarding patient reported symptom control, serum biomarkers, nasal polyp score (NPS), and sense of smell were analysed over a course of up to 30 months. Results: 96 patients from 8 tertiary treatment centers were included, 36.5% female, with a mean age of 54.1±14.3 years. Patient reported outcome measures, smell, and NPS improved significantly within 6 months after treatment initiation or switch from a different biological to mepolizumab. Change from baseline in outcome parameters was smaller in the switch-group, whereas comorbid asthma indicated greater treatment success. Conclusions: Our real-world data show a sustained therapeutic effect of mepolizumab in CRSwNP, including a large proportion of patients who were previously treated with a different biological. This study is the largest real-world cohort to date depicting realistic treatment and disease situations, confirming a broad range of indication for mepolizumab in severe CRSwNP.