The emergency of biologics and surgical techniques targeting the specific inflammatory endotype in chronic rhinosinusitis with nasal polyps (CRSwNP) asks for efficient identification of patients with different endotypes. Although mucosal IL-4, IL-5, IL-13, and IgE have been used to define type 2 (T2) inflammation, the optimal one remains unclear. In this study, we aimed to determine the optimal anchor for T2 inflammation and identify clinical characteristics and nasal secretion biomarkers predicting different endotypes in CRSwNP.Six mediators in sinonasal tissue and 36 mediators in nasal secretion samples were detected by the Bio-Plex suspension array system. Mucosal IFN-γ and IL-17A levels were used to define the T1 and T3 endotype, respectively. The efficacy of mucosal IL-4, IL-5, IL-13, and IgE to define the T2 endotype was compared. The power of clinical characteristics and nasal secretion biomarkers to predict the T1, T2, and T3 endotype was analyzed.Among mucosal IL-4, IL-5, IL-13, and IgE, IL-13 was the best one to coincide with the expression of other T2 biomarkers. A combination of atopy, facial pain symptom score, ethmoid/maxillary computed tomography score ratio, and blood eosinophil percentage had a moderate predictive performance for T2 endotype (area under the receiver operating curve [AUC] = 0.815), comparable to that of nasal secretion IL-5 (AUC = 0.819). For the T3 endotype, nasal secretion IL-1Rα identified it with an AUC value of 0.756. No efficient marker for the T1 endotype was found.IL-13 is a primary anchor for the T2 endotype in CRSwNP. Clinical characteristics and nasal secretion biomarkers are helpful for identifying the T2 and T3 endotype of CRSwNP.© 2023 The Author(s). Published by S. Karger AG, Basel.