BACKGROUND Sinonasal inverted papilloma (IP) is a rare and benign epithelial tumor in the sinonasal tract. Recent study suggested the potential role of chronic inflammation in the pathogenesis of IP. This study aims to compare the inflammatory pattern, the capacity of epithelial cell proliferation and EGFR mutation status of unilateral IP with contralateral polyp tissue. METHODS Sixteen patients with unilateral IP and contralateral nasal polyps (NP) were identified through a retrospective chart review. The neutrophil and eosinophil infiltration in IP and NP were assessed by immunostaining for neutrophil elastase and major basic protein (MBP). Immunohistochemistry was also used to assess the expression of FoxM1, Ki67 and cyclin D1 in IP tissue and contralateral NP. Sanger sequencing was used to evaluate the EGFR mutations. RESULTS The neutrophil count in IP was significantly higher than contralateral NP and 68.8% patients presented with neutrophilic inflammation, whereas only 37.5% contralateral NP tissue showed neutrophilic inflammation. The percentage of positive FoxM1-staining cells was significantly increased in IP, and positively correlated with the percentage of cells with positive staining for cyclin D1 and ki67 as well as neutrophil counts. EGFR exon 20 insertions were detected in 14 (87.5%) IP samples and no EGFR mutations were found in contralateral NP sample. CONCLUSIONS Our study demonstrated distinct inflammatory pattern between IP and contralateral NP and implied the oncogenic role of neutrophils in the pathogenesis of IP. EGFR mutations may be the early event to initiate IP development by enhancing epithelial cell proliferation.