Intracortical microelectrodes are used both in basic research to increase our understanding of the nervous system and for rehabilitation purposes through braincomputer interfaces to restore motor function lost to injury or disease. Yet, recording instability prevents the widespread clinical use of this technology. One of the causes of recording instability is the biological response to the devices. The initial insertion of the electrode probe results in implantation damage leading to the inflammatory response initiated by the innate immune system. The overall goal of this work was to examine the role of the innate immune response, with special emphasis on the role of Cluster of Differentiation 14 (CD14), in the foreign body response to intracortical microelectrodes. Since a detailed analysis of the innate immune response directly after intracortical microelectrode implantation has not been explored, we characterized the molecular sequelae of the acute innate immune response. The gene expression profiles of brain tissue around an implanted microelectrode were analyzed at 4 different time points within the first 2 weeks post implantation. Special emphasis was placed on genes involved in the complement system, cytokine response and chemokine response. The Toll-like receptor pathway and pattern recognition receptors were also examined in detail. Differential gene expression analysis compared to sham revealed 26 genes involved in the acute innate immune response which could inform future therapeutic targets. Since Itgam, Cd14, and Irak4 were all strongly upregulated compared to sham and involved in different aspects of the innate immune response, they provide a starting point for promising therapeutic strategies. Additionally, we explored the effects of targeting CD14 coupled with targeting another cause of failure of intracortical microelectrodes, the mechanical mismatch between the stiff silicon probe and the brain. To decrease the mechanical mismatch, a probe that softened after being implanted into the brain was used. Unexpectedly, we found that the softening substrate increased the neuroinflammatory response compared to stiff control probes. However, these results are attributed to the softening probe having 4x the cross-sectional area as the control silicon probe. This discrepancy in probe size was a large limitation to this study. In this study, we demonstrated that this type of softening material with and without targeting CD14 was not able to overcome the increased inflammation driven by large penetration profile differences. These findings highlight that size of the implant is a very important consideration in intracortical microelectrode design and combining multiple strategies is necessary for the successful improvement of intracortical microelectrodes. Our results also indicated that completely knocking out CD14 resulted in higher neuronal density and decreased glial scar at two weeks post probe implantation, characterizing the acute benefits of targeting CD14. The results of this work support the importance of CD14 pathway as a mechanism amenable for therapeutic targeting. Lastly, we examined the role of CD14 on the two major types in which it is expressed—infiltrating macrophages and microglia—using a bone marrow chimera mouse model to selectively knock out CD14 from either of these two cell types. We tracked the ability of implanted multichannel intracortical microelectrodes to record single units from the cortex of these animals. Results indicated that removing CD14 from the blood-derived macrophages improves intracortical microelectrode recording quality over the 16 week long study. Future studies could explore the delivery of a small-molecule inhibitor to CD14 or antiCD14 antibody as more clinically relevant methods to target CD14 on blood-derived cells.