The cell surface receptor protein tyrosine phosphatase mu (PTPmicro) is a homophilic cell adhesion molecule expressed in CNS neurons and glia. Glioblastomas (GBMs) are the highest grade primary brain tumors with astrocytic similarity and are characterized by marked dispersal of tumor cells. PTPmicro expression was examined in human GBM, low-grade astrocytoma, and normal brain tissue. These studies revealed a striking loss of PTPmicro protein expression in highly dispersive GBMs compared to less dispersive low-grade astrocytomas and normal brain. We hypothesized that PTPmicro contributes to contact inhibition of glial cell migration by transducing signals in response to cell adhesion. Therefore, loss of PTPmicro may contribute to the extensive dispersal of GBMs. The migration of brain tumor cells was assessed in vitro using a scratch wound assay. Parental U-87 MG cells express PTPmicro and exhibited limited migration. However, shRNA-mediated knockdown of PTPmicro induced a morphological change and increased migration. Next, a brain slice assay replicating the three-dimensional environment of the brain was used. To assess migration, labeled U-87 MG glioma cells were injected into adult rat brain slices, and their movement was followed over time. Parental U-87 MG cells demonstrated limited dispersal in this assay. However, PTPmicro shRNA induced migration and dispersal of U-87 MG cells in the brain slice. Finally, a mouse xenograft model of intracranially injected U-87 MG cells was used. PTPmicro shRNA induced morphological heterogeneity in these xenografts. Together, these data suggest that loss of PTPmicro in human glioblastomas contributes to tumor cell migration and dispersal, implicating loss of PTPmicro in glioma progression.