Using quantitative immunohistological methods, we examined the brain tissue response to hollow fiber membranes (HFMs) that were either implanted intraparenchymally, as in a cell encapsulation application, or were attached to the skull as in a biosensor application (transcranially). We found that the reaction surrounding transcranially implanted HFMs was significantly greater than that observed with intraparenchymally implanted materials including increases in immunoreactivity against GFAP, vimentin, ED-1 labeled macrophages and microglia, and several extracellular matrix proteins including collagen, fibronectin, and laminin. In general, these markers were elevated along the entire length of transcranially implanted HFMs extending into the adjacent parenchyma up to 0.5 mm from the implant interface. Intraparenchymal implants did not appear to have significant involvement of a fibroblastic component as suggested by a decreased expression of vimentin, fibronectin and collagen-type I at the implant tissue interface. The increase in tissue reactivity observed with transcranially implanted HFMs may be influenced by several mechanisms including chronic contact with the meninges and possibly motion of the device within brain tissue. Broadly speaking, our results suggest that any biomaterial, biosensor or device that is anchored to the skull and in chronic contact with meningeal tissue will have a higher level of tissue reactivity than the same material completely implanted within brain tissue.