Summary: Interictal spikes are hallmarks of epileptic neocortex that are used commonly in both EEG and electrocorticography (ECoG) to localize epileptic brain regions. Despite their prevalence, the exact relationship between interictal spiking and the molecular pathways that drive the production and propagation of seizures is not known. We have recently identified a common group of genes induced in human epileptic foci, including EGR1, EGR2, c-fos, and MKP-3. We found that the expression levels of these genes correlate precisely with the frequency of interictal activity and can thus serve as markers of epileptic activity. Here, we explore this further by comparing the expression of these genes within human epileptic neocortex to both ictal and specific electrical parameters of interictal spiking from subdural recordings prior to surgical resection in order to determine the electrical properties of the human neocortex that correlate best to the expression of these genes. Seizure frequency as well as quantitative electrophysiological parameters of interictal spikes including frequency, amplitude, duration, and area were calculated at each electrode channel and compared to quantitative real-time RT-PCR measurements of four activity-dependent genes (c-fos, EGR1, EGR2, and MKP-3) in the underlying neocortical tissue. Local neocortical regions of seizure onset had consistently higher spike firing frequencies and higher spike amplitudes compared to nearby “control” cortex. In contrast, spike duration was not significantly different between these two areas. There was no relationship observed between seizure frequency and the expression levels of activity-dependent genes for the patients examined in this study. However, within each patient, there were highly significant correlations between the expression of three of these genes (c-fos, EGR1, EGR2) and the frequency, amplitude, and total area of the interictal spikes at individual electrodes. We conclude that interictal spiking is closely associated with the expression of a group of activity-dependent transcription factors in neocortical human epilepsy. Since there was little correlation between gene expression and seizure frequency, our results suggest that interictal spiking is a stronger driving force behind these activity-dependent gene changes and may thus participate in the development and maintenance of the abnormal neuronal hyperactivity seen in human epileptic neocortex.