BackgroundOlfaction is one of the important senses for humans. Systemic glucocorticoids are the most commonly used medications for olfactory loss because of their strong anti-inflammatory effects. However, their effect on olfactory function is still controversial and the precise mechanism is not clear. To gain a global view of the effect of systematic glucocorticoid treatment on gene expression in the olfactory mucosa (OM), we profiled these changes in a murine model of olfaction in order to identify underlying molecular mechanisms. MethodsC57BL/6 mice were injected daily for 2 weeks (WK2) with dexamethasone (DEX, intraperitoneally, 1 mg/kg body weight) vs 1 day of DEX (D1) vs controls, which received saline (Ctrl) (n = 9/group). Total RNA from the OM was used to analyze global gene expression. Genes showing changes in expression were compared using the Database for Annotation, Visualization and Integrated Discovery (DAVID, v6.7) and the General Olfactory Sensitivity Database (GOSdb; ). ResultsBetween the WK2 and Ctrl groups, 3351 genes were differentially expressed, of which 236 genes were related to olfactory function. Genes involved in axon guidance, cell projection, and inflammation were enriched and overlapped significantly with those in the GOSdb. ConclusionSystemic glucocorticoids exert effects on transcription of a notable number of genes in the OM and appear to orchestrate changes related to axon guidance, cell projection, and inflammation. Further examination may allow targeted therapies that lack the side effects of this category of medication.