SH-PTP2 is a protein-tyrosine phosphatase with src homology-2 (SH2) domains and shown to be highly expressed in the rat brain. Light microscopic immunohistochemistry showed that specific immunoreactivity was widely distributed, most abundant in neurophil, weak in neuronal somata, and absent from white matter. By electron microscopic immunohistochemistry, intense labeling is observed on synapses and concentrated in the pre- and post-synaptic plasma membranes. In subcellular fractionation analysis of brain, SH-PTP2 was mainly observed in the particulate fraction, particularly in myelin and synaptosomes. SH-PTP2 was further recovered in the synaptic plasma membrane. SH-PTP2 was extracted from brain membrane with a detergent such as Triton X-100 or Nonidet P-40 but not with 1 M NaCl. Furthermore, SH-PTP2 was coimmunoprecipitated with a 100 kDa tyrosine-phosphorylated membrane protein, which may couple SH-PTP2 to brain membranes. These results suggest that SH-PTP2 associates with synaptic membranes and may play a role in the synaptic communications in the brain.