In order for neural prosthetics to transition into the clinic, the microelectrode arrays on which they rely must function reliably in vivo for clinically relevant time periods. However, to date studies have shown that functional longevity in these devices is limited. An understanding of what causes these devices to fail is imperative for the development of more reliable arrays. Although studies have evaluated electrophysiological signals or histological responses in an attempt to explain device failure, to our knowledge no group has correlated histopathological outcome with electrophysiological signal quality. To address this issue, we implanted a 100 shank Utah Electrode Array (UEA) into the motor cortex of a cat. Wide-band electrophysiological signals were recorded over the course of eight months. Action potential waveforms from single neurons were isolated from the recordings using standard spike sorting algorithms, and several metrics of signal quality were calculated using the obtained data. On the day of the final recording, the animal was sacrificed and subsequently, histological examination of the neural tissue containing the array was performed. Cortical tissue was horizontally sectioned in 40 μm increments and the spatial distribution of NeuN and Isolectin B4 was analyzed using immunofluorescent methods and image analysis. Electrophysiological signal quality data and histological response data were examined for correlations. No correlation was evident between neuronal density and single units as a function of electrode location, suggesting that while proximity of at least one neuron is required for recording, the presence of neurons is not sufficient to ensure functionality. In contrast, an inverse correlation between the inflammatory biomarker B4 density and electrode functionality was observed. This hints at a complex interplay between different cell types which may contribute to electrode failure, and suggests that neuronal density alone is not a good predictor of recording quality. This study provides evidence that inflammatory cells or their secreted products may negatively affect recording ability and the function of micro-electrodes, even in the presence of viable neurons. Furthermore, this study demonstrates the importance of evaluating both histology and electrophysiology in an effort to better understand the underlying mechanisms which may lead to failure of implanted micro-electrode arrays in nervous tissue.