Chronic rhinosinusitis with nasal polyps (CRSwNP) is amultifactorial inflammatory disease, the treatment of which has undergone significant changes in recent years. In addition to surgical approaches, topical and systemic steroids, and adaptive acetylsalicylic acid (ASA) desensitization, three specific antibodies have complemented the therapeutic portfolio since 2019. Aretrospective evaluation of all patients who presented as outpatients for the first time due to CRSwNP in 2007 and 2008 (collectiveA) and 2017 and 2018 (collectiveB) was performed, up to and including June 2023. The clinical courses of 463patients (mean age 49.1years, range 5-82years; 65.9% male) were included in the analysis. Conservative treatment with nasal corticosteroids started before initial presentation was more frequent in collectiveB (collectiveA 43.9% vs. collectiveB 72.2%). In 278 of the 463 patients (60%; A:62%, B:58%), at least one operation on the nasal sinuses had been performed after initial presentation; in 101 of these patients (36.3%) recurrent polyposis (within mean follow-up of 2.4years) required further treatment. The indication for ASA provocation/desensitization was applied less frequently in collectiveB, also due to ahigh discontinuation rate (at least 38%) of the maintenance therapy. Of the total cohort, 16patients (3.5%; A:n = 8, B:n = 8) were meanwhile switched to antibody therapy at recurrence. Astep-by-step guideline-orientated approach is recommended in the treatment of CRSwNP. Systemic antibodies as an add-on to nasal corticosteroids are arelatively new therapeutic option for treatment-refractory CRSwNP, which reduces the indication for ASA desensitization, which is associated with a relatively high incidence of side effects and poor compliance.