ABSTRACTObjectiveEvaluating the possibility of predicting chronic rhinosinusitis with nasal polyps (CRSwNP) disease course using Artificial Intelligence.MethodsWe prospectively included patients undergoing first endoscopic sinus surgery (ESS) for nasal polyposis. Preoperative (demographic data, blood eosinophiles, endoscopy, Lund‐Mackay, SNOT‐22 and depression PHQ scores) and follow‐up data was standardly collected. Outcome measures included SNOT‐22, PHQ‐9 and endoscopy perioperative sinus endoscopy (POSE) scores and two different microRNAs (miR‐125b, miR‐203a‐3p) from polyp tissue. Based on POSE score, three labels were created (controlled: 0–7; partial control: 8–15; or relapse: 16–32). Patients were divided into train and test groups and using Random Forest, we developed algorithms for predicting ESS related outcomes.ResultsBased on data collected from 85 patients, the proposed Machine Learning‐approach predicted whether the patient would present control, partial control or relapse of nasal polyposis at 18 months following ESS. The algorithm predicted ESS outcomes with an accuracy between 69.23% (for non‐invasive input parameters) and 84.62% (when microRNAs were also included). Additionally, miR‐125b significantly improved the algorithm's accuracy and ranked as one of the most important algorithm variables.ConclusionWe propose a Machine Learning algorithm which could change the prediction of disease course in CRSwNP.