Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disorder characterized by exaggerated local immune responses. Tumor necrosis factor--induced protein 8-like 2 (TIPE2) is a novel protein with potential immune modulating function. The expression and function of TIPE2 in human airway diseases are unclear. Methods: The expression of TIPE2 in sinonasal mucosal samples was assessed by means of quantitative reverse transcript-polymerse chain reaction, immunohistochemistry, and Western blotting. The human monocytic/macrophage cell line, THP-1 cells, was stimulated with various cytokines. Computed tomography (CT) scan images, endoscopic findings, and symptoms were scored. Results: Compared with non-eosinophilic polyps and control mucosa, the mRNA and protein expression of TIPE2 was significantly upregulated in eosinophilic polyps, with a further increase in those with asthma. The number of CD68(+)CD163(+) alternatively activated (M2) macrophages was increased in eosinophilic polyps. TIPE2 was mainly expressed by M2 macrophages in sinonasal mucosa and its expression was upregulated in M2 macrophages in eosinophilic polyps. Interleukin (IL)-4 and IL-13, but not interferon (IFN)- or IL-17A, induced TIPE2 expression in differentiated THP-1 cells. The mRNA levels of IL-4 and IL-13 correlated with the mRNA levels of TIPE2 and M2 macrophage markers in sinonasal mucosa. Importantly, the number of TIPE2(+) cells, particularly TIPE2(+)CD163(+)CD68(+) M2 macrophages, correlated positively with the number of eosinophils and total inflammatory cells in sinonasal mucosa, as well as disease duration, CT scores, hyposmia scores, and polyp size in CRSwNP. Conclusion: The T-helper 2 milieu is able to induce TIPE2 expression in macrophages. TIPE2-positive M2 macrophages potentially contribute to eosinophilic inflammation and disease progression in CRSwNP. (C) 2017 ARS-AAOA, LLC.