The cortex of an entire cerebral hemisphere in the cat was chronically isolated to allow assessment of the role of intrinsic association pathways in the regulation of focal epileptic activity induced by topical application of penicillin. EEG recordings indicated that interictal spike activity in the normal hemisphere was maximal at the focus and markedly reduced in amplitude at distances of 5 to 7 mm. Activity in the isolated hemisphere was similar in morphology to that of the normal cortex, but there were largeamplitude epileptiform discharges 10 to 15 mm from the focus. These distant penicillin spikes appeared early in the development of the focus and were not attributable to diffusion of penicillin. Intracellular recordings at the center of the focus and at remote sites showed the characteristic paroxysmal depolarizing shifts (PDSs) previously described for intact cortex, i.e., large-amplitude membrane depolarizations with superimposed high-frequency spike activity and subsequent spike inactivation. Hyperpolarizing potentials followed termination of PDSs in most cells and were occasionally seen as the sole accompaniment of the focal penicillin discharges. We suggest that the similarity of intracellular findings in normal and isolated cortices could have resulted from a direct effect of penicillin on neurons, whereas the spread of interictal spikes in the isolated hemisphere apparently involved abnormal utilization of existing intracortical association pathways. © 1978.