This study demonstrates the expression of the novel protein protein tyrosine phophatase-interacting protein 51 (PTPIP51) in mammalian brain tissue. Serial sections of the whole adult mouse brain were analyzed for PTPIP51 protein and mRNA by immunohistochemistry, immunoblotting, RT-PCR, and in situ hybridization. Recent investigations by Yu et al. (2008) describe PTPIP51 as being capable of activating Raf-1, thereby modulating the MAPK pathway. The role of Raf-1, as well as of 14-3-3, in neurological disorders is well established. PTPIP51 expression was confined to neurons in the following structures: the piriform cortex and their connections to the anterior commissure, nucleus accumbens, paraventricular and supraoptical nuclei, neurohypophysis, superior colliculus, genu of facialis nerve, spinal trigeminal tract, inferior cerebellar peduncle, and cerebellum. In the cerebellum, a subpopulation of Purkinje cells and their dendrites was strongly PTPIP51 positive. Moreover, PTPIP51 was found to be colocalized with vasopressin and its transport protein neurophysin II in the neuroendocrine nuclei and their connections to the neurohypophysis. The data presented here suggest a role of PTPIP51 in neuronal homeostasis, axonal growth, and transport.