Objectives/HypothesisEmpty nose syndrome (ENS) is a controversial disorder and the change of histopathology has never been discussed. This study aimed to conduct a structured histological review to improve the diagnosis and understanding of ENS. Further immunohistochemical staining of transient receptor potential channel melastatin 8 (TRPM8) was performed.Study DesignA prospective case–control study in a tertiary medical center.MethodsConsecutive patients with ENS who were diagnosed and received surgical intervention after failure of conservative management were included. Patients with benign pituitary gland tumor receiving transsphenoidal excision were enrolled as control group. Biopsy of inferior turbinate was obtained during surgery for histological review and immunohistochemical staining.ResultsSeventeen patients with ENS and six patients as a control group were established for structured histological review. Patients with ENS presented significantly more squamous metaplasia, a higher rate of submucosal fibrosis, and a lower submucosal gland number grading. Additionally, a unique histological change called goblet cell metaplasia was found in the ENS group. The respiratory epitheliums of ENS were mostly intact with preservation of ciliated cells and goblet cells. The ENS group had a significantly lower expression level of TRPM8.ConclusionsThe nasal mucosa of ENS experienced some airway remodeling and thermoreceptors downregulation, which contribute to clinical symptoms. The distinct histology of ENS included preserved respiratory epithelium and goblet cell metaplasia, accompanying with characteristics similar to atrophic rhinitis. Biopsy of the inferior turbinate may help diagnose ENS.Level of Evidence4 Laryngoscope, 131:E14–E18, 2021