AbstractObjectivesSuccessful recovery from chronic rhinosinusitis (CRS) following endoscopic sinus surgery (ESS) can be characterized by minimal presence of symptoms and absence of disease on endoscopy. However, molecular markers of surgical success remain to be characterized. These could allow for better tailoring of perioperative therapy. This study aims to identify novel molecular markers associated with surgery responsive patient.Study DesignProspective cohort study.SettingSingle academic hospital center.MethodOne hundred eighteen consecutive patients with CRS at high risk of recurrence after surgery were followed prospectively following ESS in an academic medical center. Symptomatic and endoscopic outcomes were assessed at 4 months, with success rigorously defined subjectively as minimal or no symptoms (no symptom greater than 1 on an ordinal scale of 0‐3) and objectively by the absence of nasal polyposis on sinus cavity endoscopy and Lund‐Kennedy endoscopic edema score no greater than 1. Samples were obtained at the time of surgery and at 4‐month postoperatively. Changes associated with surgery were determined by gene expression profiling using Affymetrix's Clariom S Human HT arrays.ResultsSuccessful ESS was characterized by a mild upregulation in Type 1 inflammation, upregulation of cell cycle progression, and epithelial barrier and proliferation‐associated genes and pathways. ESS failure was associated to very high levels of Type 1 inflammation along with downregulation of epithelial barrier function and regeneration genes and pathways.ConclusionSuccessful recovery from ESS involves restoration of epithelial function and regulated activation of Type 1 inflammation. Excessively elevated Type 1 inflammation is associated with epithelial barrier dysfunction.