Background: Integrated care pathways improve the management of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The application of integrated care pathways requires development of endotype-based biomarkers to stratifypatients. The value of cytokines and markers induced by cytokines for the management of CRSwNP is largely unknown. Objectives: Our aim was to determine the prognostic and pharmacologic value of type 2, non-type 2 cytokines, and markers associated with type 2 inflammation, including CCL26, periostin, and cystatin SN, in nasal secretions for CRSwNP. Methods: This retrospective study assigned 151 patients with CRSwNP to the discovery and validation phases. Concentrations of cytokines, CCL26, periostin, and cystatin SN in nasal secretions were determined by using Luminex and ELISA. Predictive significance was assessed with receiver operating characteristic curves. Survival analysis was performed by using Kaplan-Meier curves and Cox regression models. Results: Cystatin SN was an independent predictor of the uncontrolled status of CRSwNP over a 2-year follow-up after adjustment for other risk factors (hazard ratio = 1.168 and 1.132 in the discovery and validation phases, respectively; both P < .001). Patients with high cystatin SN concentrations presented with a faster onset and higher rate of uncontrolled status than did those with low levels (P < .001). Enhanced medical treatment for patients with high cystatin SN levels postponed the uncontrolled status in the discovery (P = .016) and validation (P = .002) phases but did not completely abolish it by the end of the follow-up. Conclusion: Cystatin SN levels in nasal secretions hold strong prognostic value and can facilitate medical instructions for managing CRSwNP.