Background: The origin and pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. Glycogen synthase kinase 3 (GSK-3) is a unique multitasking kinase involved in the regulation of inflammation and apoptosis and is an important messenger in the downstream signaling of interleukin 6. Objective: To analyze the possible role of GSK-3 in the pathogenesis of CRSwNP. Methods: We examined tissue samples of nasal polyps and the inferior turbinate of patients with CRSwNP and the inferior turbinate of individuals without chronic sinusitis (healthy mucosa). Expression levels of GSK-3 and its inactivated form phosphorylated GSK-3 (pGSK-3) were analyzed using DNA microarray, protein array, Western hybridization, and immunohistochemical analysis. Results: We found increased expression of GSK-3 in both the nasal polyps and the inferior turbinate of patients with CRSwNP compared with those with healthy mucosa (P <.01). We did not observe a difference between nasal polyps and the inferior turbinate of patients with CRSwNP, but a highly significant increase in the phosphorylation rate of GSK-3 was detected in the tissue of nasal polyps compared with the turbinates of patients with CRSwNP (P <.01). Conclusion: GSK-3 may play a crucial role in the inflammatory process in CRSwNP. Nasal polyps originate mainly in the mucosa of the middle meatus of the nose and rarely occur in the region of the inferior turbinate. The inhibition of GSK-3 by phosphorylation in nasal polyps, in contrast to the inferior turbinate, is a possible explanation for the different behavior of the mucosa of the middle meatus and the inferior turbinate.