Epileptic foci were established by application of Na-penicillin on the exposed parietal cortex of rats (n=66) anesthetized with pentobarbital. Spikes appearing after a brief (>30s) spontaneous interruption of the interjetal discharge were sometimes followed by a spike-triggered spreading depression (STSD) wave, which blocked the activity of the focus for several min. The first recovering spike induced another STSD and repetitive STSD generation continued for up to 20 cycles, with a median cycle duration of 6 min. STSDs appeared more regularly after postictal depression induced by electrical stimulation of the focus or of the symmetrical brain area, and could also be elicited by SD waves evoked by microinjection of 5% KCl into extrafocal cortical regions. An ongoing STSD cycle was interrupted when another penicillin focus in the contralateral hemisphere started to trigger the focal discharge during relative SD refractoriness. STSD waves were observed in 42% of the animals. Attempts to elicit STSD were successful in 70% when the interictal discharge rate was low (<10/min) but mostly failed with higher discharge rates (>30/min). It is suggested that STSD is generated when an isolated epileptic spike appears at the level of decreased potassium clearance and. that repetitive STSDs are produced by synaptically and metabolically mediated interaction between focal discharge and spreading depression.