Background:The treatment of refractory chronic rhinosinusitis with nasal polyps (CRSwNP) withomalizumab has been well studied based on clinical evaluation. Nevertheless, ideal quantitative orqualitative biomarkers for predicting a different response to biologics urgently need to beexplored. We aim to identify potential biomarkers for predicting a good or poor response in pa-tients with refractory CRSwNP. Methodology:Patients received an endoscopic and radiological evaluation, a visual analoguescale (VAS) assessment, and a 22-item sinonasal outcome test (SNOT-22). Forty-eight biomarkersinvolving type 1 (T1), type 2 (T2), and type 3 (T3) inflammatory factors, chemokines, andremodeling factors were detected in nasal secretion and serum samples at baseline and after 24weeks of omalizumab treatment. Results:Eighteen patients with CRSwNP and 16 patients as control were enrolled. Patients withCRSwNP who received oamlizumab treatment with the SNOT-22 and VAS scores improved by 8.9and 2 points in 72.22% and 50%, respectively.The nasal polyp score (NPS) and Lund-Mackay scorewere significantly improved in 55.56% of patients. The concentrations of T2 inflammatorybiomarker, granulocyte-macrophage colony-stimulating factor (GM-CSF), T3 inflammatory bio-markers, granulocyte colony-stimulating factor (G-CSF), chemokine (C-X-C motif) ligand (CXCL)-1,and chemokine (C-C motif) ligand-20 (CCL-20), T1 inflammatory biomarker, IP-10 (CXCL-10), andgranzyme B in nasal secretion and serum periostin were significantly decreased. Serum CCL-3(AUC 1/40.836) and CCL-4 (AUC 1/40.909) levels predicted the improvement of SNOT-22 score,respectively. Serum IL-8 (AUC 1/40.883) predicted poor improvement in nasal congestion score.Nasal secretion CXCL-1 (AUC 1/40.812), GM-CSF (AUC 1/40.813), IgE (AUC 1/40.900) and IP-10(AUC 1/40.800) effectively predicted none or less improvement in nasal polyp score. Conclusions:Omalizumab remarkably affects inflammatory mediators in different pathways.CCL-3 and CCL-4 in serum and IgE, CXCL-1, GM-CSF, and IP-10 in nasal secretion may be considered as preferable biomarkers for predicting favorable or ineffective response to omalizu- mab therapy in patients with refractory CRSwNP comorbid with asthma, based on various clinical indicators.