Silicon microelectrode arrays (SiMEAs) implanted in the brain are able to record action potentials from nearby neurons for long periods of time and have been shown to have the potential of helping patients suffering from limited mobility. However, after over 50 years of studying the tissue reaction surrounding implanted electrodes and more recently implanted SiMEAs, the factors that affect the subsequent brain tissue response remain unknown. Therefore, a clear rationale for the present generation of implanted electrode arrays is unclear. We have consistently observed evidence of persistent inflammation and neuronal loss in the recording zone at the biotic-abiotic interface irrespective of the type of implanted electrode, array assembly, and age of the animal, which appears similar in rat and cat. In this study, we sought to more fully understand the relationship between device surface geometry and the long-term foreign body response. Towards this end, we compared the tissue response to cylindrical single shaft electrodes, planar SiMEAs and Utah electrode arrays using quantitative image analysis and a similar set of cell type specific markers. All electrodes were implanted under sterile conditions and sacrificed at time points of at least 12 weeks post-implantation by transcardial perfusion with 4% paraformaldehyde. Sections of brain tissue were analyzed for the glial markers, GFAP and ED-1, and the neuronal markers NeuN, and either NF-200 or NF-160. Consistently, the glial and neuronal reactions we observed mirrored the geometry of the implanted device and its orientation supporting the hypothesis that the geometry of the exposed surface area of the device is the major stimulus of persistent macrophage activation and its associated inflammatory sequelae. Circular devices showed circular patterns of reactivity, while planar device geometries showed an elliptical pattern of local tissue reactivity whose orientation was changed by a priori changing the orientation of the implanted device. Areas of device assemblies with the greatest density of exposed surface area showed the greatest amount of periprosthetic inflammation with associated cell loss and glial scarring. Likewise, devices with less exposed surface area showed reduced glial reactivity suggesting that the rationale for the next generation of microelectrode array designs should be based on reducing the inflammatory footprint of the device.