Objective To investigate the expression and localization of receptor expression-enhancing protein 2(REEP2) protein throughout the adult mouse brain, providing essential anatomical insights into its physiological functions and mechanistic involvement in hereditary spastic paraplegias (HSP). Methods An integrated approach combining Human Protein Atlas (HPA) database analysis and immunohistochemical techniques were employed. Brain sections from 6 adult mice were used for REEP2 immunohistochemical staining. Whole-brain section imaging was acquired using a digital scanning microscopic imaging system, with precise anatomical identification and localization of positively expressed regions based on the standard mouse brain atlas. Results REEP2 protein was widely expressed in the brains of adult mice, including the cerebral cortex, thalamus, cerebellum, and hippocampus. Localization and analysis of REEP2-positive regions and cells revealed its predominant expression in neuronal cell bodies and dendrites, with all REEP2-positive structures appearing as brownish-yellow granules. Notably, high expression was observed in pyramidal neurons of the cerebral cortex, caudate and putamen neurons of the basal ganglia, the ventral posterior medial and lateral nuclei of the thalamus, and the lateral nucleus group of the thalamus (e.g., the lateral posterior nucleus neurons) as well as cerebellar Purkinje cells. In hippocampal neurons, it showed moderate expression. Conclusion REEP2 protein is enriched in several brain regions, e.g. cortex, cerebellum, striatum, thalamus, hippocampus, etc. This study elucidates the spatial expression profile of REEP2 protein in the adult mouse brain. The findings provide crucial morphological evidence for subsequent development of conditional knockout animal models and further investigation into the role of REEP2 dysfunction in HSP pathogenesis, as well as its broader neural functions.