Chronic rhinosinusitis with nasal polyps (CRSwNP) is a mainly type-2-driven inflammatory disease that is often refractory to medical and surgical treatment and characterized by a high rate of recurrence. Monoclonal antibodies have been approved for severe refractory CRSwNP. Randomized controlled trials (RCT) have shown significant improvement in objective and subjective parameters. The results of these RCTs cannot necessarily be transferred to daily routine. The purpose of this retrospective study is to evaluate the treatment effects of biologics in patients with CRSwNP in a real-life setting. Patients treated with one of the approved biologics since July 2020 with at least 6 months follow-up were included in the study. Changes in SNOT-22 and nasal polyp score (NPS), as well as subjective change in sense of smell, number of sinus surgeries prior to and during treatment, comorbidities, discontinuation or change of monoclonal antibody and adverse events were evaluated. Thirty-three patients were included in this study. The mean SNOT-22 score and NPS improved significantly. The subjective assessment of sense of smell showed an improvement in 81.8% of patients. The monoclonal antibody had to be changed in seven patients. No severe adverse events occurred during the initiation of the treatment and follow-up. Biologics can be a treatment option in patients with severe refractory CRSwNP, showing significant improvements in quality of life, symptoms and polyp scores in randomized controlled trials and clinical routine with rare complications. Further research is needed to evaluate possible biomarkers, interdose interval prolongation and long-term safety.