PSD-95, an abundant key component of the postsynaptic density, is known to play key roles in the organization of postsynaptic signaling complexes. To better understand the functions of PSD-95, we performed yeast two-hybrid screen and identified the interaction of PSD-95 with MTMR2, a dual-specificity phosphatase for phospholipids and tyrosine-phosphorylated proteins. Mutations in the MTMR2 gene in human patients are responsible for the autosomal recessive Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe hereditary motor and sensory neuropathy, which is predicted to be caused by the impaired development of Schwann cells that are ensheathing peripheral nerve fibers. Despite the critical role of MTMR2 in peripheral neuropathy, little is known about its function in central nervous system where it is highly expressed. MTMR2 interacts with the PSD-95 family proteins in various in vitro assays including yeast two-hybrid, pull down, coimmunoprecipitation and coclustering assays. In brain, MTMR2 forms a complex with selected members of the PSD-95 family including PSD-95, Chapsyn-110 and SAP102. In cultured neurons, MTMR2 partially distributes to synaptic sites, but is co-expressed to synaptic sites with PSD-95. These results suggest MTMR2 is targeted to synaptic sites by PSD-95 interaction and may regulate signaling pathways involved in synaptic development and function.