Abstract: Objective To explore the correlation between the expression of cAMP response element-binding protein 2 (CREB2) and olfactory marker protein (OMP) in the olfactory mucosal epithelium and olfactory disorders in patients with chronic rhinosinusitis (CRS). Methods A total of 25 CRS patients with olfactory disorders who were admitted to the Affiliated Hospital of Xuzhou Medical University from September 2021 to March 2022 were selected as an observation group. Meanwhile, additional 15 patients with nasal septum deviation and normal olfaction were chosen as a control group. Preoperative olfactory function was assessed in both groups using the sniffin' sticks TDI scoring system. During surgery, olfactory mucosal tissues were collected as specimens. The levels of CREB2 and OMP in the olfactory mucosal epithelium were detected using immunohistochemistry and Western blot, and their correlation with olfactory function was analyzed. Results The TDI scores in the observation group were significantly lower than those in the control group (P<0.05). Immunohistochemistry and Western blot results showed that the number of CREB2 and OMP positive cells and their protein expression levels in the olfactory mucosa significantly decreased in the observation group, compared with the control group (P<0.01). The levels of CREB2 and OMP in the olfactory mucosal epithelium were positively correlated with TDI scores (r=0.974, P<0.01; r=0.959, P<0.01). Conclusions The decreased expression of CREB2 and OMP in the olfactory mucosal epithelium of CRS patients with olfactory disorders is positively correlated with TDI scores. Therefore, reduced expression of CREB2 in the olfactory mucosal epithelium may be associated with the molecular mechanism of olfactory disorders in CRS patients.