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As the field of neuroprosthetic research continues to grow, studies describing the foreign body reaction surrounding chronic indwelling electrodes or microelectrode arrays will be critical for assessing biocompatibility. Of particular importance is the reaction surrounding penetrating microelectrodes that are used to stimulate and record from peripheral nerves used for prosthetic control, where such studies on axially penetrating electrodes are limited. Using the Utah Slant Electrode Array and a variety of histological methods, we investigated the foreign body response to the implanted array and its surrounding silicone cuff over long indwelling periods in the cat sciatic nerve. We observed that implanted nerves were associated with increased numbers of activated macrophages at the implant site, as well as distal to the implant, at all time points examined, with the longest observation being 350days after implantation. We found that implanted cat sciatic nerves undergo a compensatory regenerative response after the initial injury that is accompanied by shifts in nerve fiber composition toward nerve fibers of smaller diameter and evidence of axons growing around microelectrode shafts. Nerve fibers located in fascicles that were not penetrated by the array or were located more than a few hundred microns from the implant appeared normal when examined over the course of a year-long indwelling period.