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Background Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) exhibits a poorer outcome compared with non-eosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP), so it is significant to identify effective markers to differentiate ECRSwNP in guiding the treatment strategies of these patients. Although arachidonate 15-lipoxygenase (ALOX15) is positioned as a marker of eosinophilic inflammation, its study in differentiating ECRSwNP has not been reported. The aim of this study is to assess the potential of ALOX15 in distinguishing and predicting ECRSwNP. Methods Forty-eight patients with chronic rhinosinusitis with nasal polyps (CRSwNP), including 30 ECRSwNP and 18 nonECRSwNP patients, were enrolled. ALOX15 mRNA level was determined in polyps by real-time polymerase chain reaction (RT-PCR). The patients’ baseline characteristics were evaluated and analyzed for correlations with ALOX15. Receiver operating characteristic (ROC) curve was used to assess the predictive significance of the potential predictors for ECRSwNP. Results ALOX15 mRNA level was significantly higher in ECRSwNP patients than in nonECRSwNP patients (P r = 0.565, P r = 0.395, P = 0.006), olfaction scores (r = 0.400, P = 0.005), total visual analogue scale (VAS) symptom scores (r = 0.383, P = 0.007), ethmoid/maxillary sinus (E/M) ratio (r = 0.463, P = 0.001), and endoscopy scores (r = 0.409, P = 0.004). Logistic regression analysis showed ALOX15 mRNA level and percentage of blood eosinophils to be predictive factors for ECRSwNP (P = 0.004 and P = 0.036, respectively). ROC curve indicated ALOX15 to have high predictive accuracy for ECRSwNP (area under the curve (AUC) = 0.909), which was further improved by combination of ALOX15 with percentage of blood eosinophils (AUC = 0.933). Conclusions The relative ALOX15 mRNA level alone or in combination with blood eosinophils might be a reliable biomarker for predicting a diagnosis of ECRSwNP.