Interictal spikes are generated in the cerebral cortex during certain pathological conditions. In normal tissue, interictal spikes are triggered by blocking GABA(A) receptors. We studied the propensity of different areas of the cerebral cortex (including neocortex and piriform cortex) to generate spontaneous interictal spikes during block of GABA(A) receptors in slices of adult mice. Ten sequential brain slices were studied spanning most of the cerebral hemisphere. During block of GABA(A) receptors spontaneous interictal spikes were observed in all slices. Interestingly, interictal spikes recurred at different frequencies in different slices; posterior slices had a higher rate than the frontal slices (approximately 0.2 vs. 0.1 Hz, posterior vs. frontal). Multi-site recordings allowed to monitor discharges traveling across each slice and to derive cross-correlations. It became apparent that for the slices with higher frequency (i.e. posterior slices) the discharges originated in the piriform cortex and spread to the neocortex. A correlation between the frequency of the spontaneous discharges and the probability of events originating from piriform cortex was positive and significant. A further demonstration of this site of origin was provided by severing the connections between the neocortex and the piriform cortex. After interrupting these connections all the neocortical sites in the posterior slices displayed a lower frequency of discharges; similar to slower frontal slices. Meanwhile, the isolated piriform cortex of the posterior slices continued to produce higher frequency discharges. Thus, the higher frequency activity displayed by the posterior slices is intrinsically generated in the posterior piriform cortex from where it spreads to the neocortex. The results indicate that the neocortex and the piriform cortex have a distinct propensity to generate spontaneous interictal spikes, and that the more prone areas impose their activity on the less prone areas during disinhibition.