In this study we aimed to identify inflammatory patterns and predictors associated with clinical outcomes in chronic rhinosinusitis with nasal polyps (CRSwNP) patients with different blood and tissue eosinophilia. A total of 535 CRSwNP patients were enrolled, and the expression of 35 biomarkers, together with eosinophil and neutrophil counts in nasal polyps, were analyzed in a subset of 249 patients. Patients were stratified on the basis of blood (≥0.5 × 109 /L) and tissue (>10%) eosinophilia. Logistic regression models were applied to identify predictors of uncontrolled disease at least 1 year after surgery. Uncontrolled disease was defined according to the European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Among 535 patients, 38.5% showed inconsistent blood and tissue eosinophilia. In 249 CRSwNP patients, subjects with concomitant blood and tissue eosinophilia (group 1) showed marked mucosal type 2 inflammation, characterized by high levels of interleukin (IL)-5, IL-13, and eotaxin-1, whereas subjects with normal blood and tissue eosinophil levels (group 4) demonstrated significant local neutrophilic inflammation with high expression of granulocyte colony-stimulating factor and subjects with selective tissue eosinophilia (group 2) showed intermediate and mixed eosinophilic and neutrophilic inflammation. Subjects with isolated blood eosinophilia (group 3) showed low expression of vascular endothelial growth factor and IL-10. Asthma, prior sinus surgery, and blood eosinophilia were the top 3 predictors for postsurgical uncontrolled disease. For subgroup analysis, sex in group 1, asthma in group 2, tissue IL-10 and immunoglobulin E in group 3, and prior sinus surgery in group 4 were the strongest predictors of uncontrolled disease, respectively. Different blood and tissue eosinophilia revealed distinct tissue inflammatory patterns in CRSwNP patients. © 2020 ARS-AAOA, LLC.