BACKGROUND: Despite increasing dupilumab use for chronic rhinosinusitis with nasal polyps (CRSwNP), little is known about the factors influencing its use in real-world practice. We aimed to identify factors that may predict dupilumab prescription in CRSwNP patients who have undergone endoscopic sinus surgery (ESS). METHODS: A single-institution, retrospective cohort study of patients who underwent ESS for CRSwNP between 2015 and 2023 was conducted. Demographics, comorbidities, 22-item sinonasal outcome test (SNOT-22) scores, and dupilumab prescription date were extracted from patient records. Intraoperative nasal mucus cytokine levels were measured using a multiplex bead assay. Univariate logistic regression analysis was performed to identify factors associated with dupilumab prescription, and multivariate logistic regression was used to adjust for surgery date. RESULTS: A total of 299 CRSwNP patients were included, including seventy (23.4%) who were prescribed dupilumab postoperatively. Patients were more likely to be prescribed dupilumab if they had asthma (odds ratio [OR] 2.304), aspirin-exacerbated respiratory disease (AERD, OR 3.375), elevated tissue eosinophils (OR 1.005), and higher 3-month postoperative SNOT-22 scores (OR 1.027). Patients prescribed dupilumab also had greater odds of having elevated mucus interleukin (IL)-5 (OR 1.128) and IL-13 (OR 1.213). When adjusting for surgery date, associated factors included: asthma (OR 2.444), AERD (OR 3.750), allergic rhinitis (OR 1.833), higher tissue eosinophils (OR 1.005), elevated 3-month SNOT-22 scores (OR 1.028), and higher IL-5 (OR 1.123) and IL-13 (OR 1.202) levels. CONCLUSION: Asthma, AERD, allergic rhinitis, and elevated tissue eosinophil, IL-5, and IL-13 levels are predictive of dupilumab prescription in CRSwNP patients. These may serve as clinical and inflammatory biomarkers and can aid in counseling patients about expected disease trajectory.