1. Picrotoxin-(PTX) induced epileptiform activity was studied in guinea pig hippocampal slices maintained in vitro, using intra- and extracellular recording techniques. 2. The observed pattern of spontaneous and evoked epileptiform activity was quite complex. Spontaneous epileptiform events originated in the CA3 region and subsequently spread or propagated to CA1. Activation of CA1 could then reactivate CA3. This reverberation of activity was seen also following stimulation of the mossy fiber afferents from the dentate gyrus to CA3. 3. Stimulation of fibers in the stratum radiatum of the CA1 region could trigger, at short latency, epileptiform activity that either was localized in CA1 or also occurred in CA3, with a late secondary discharge in CA1. This is attributed to a backfiring of the Schaffer collaterals and illustrates the ability of a variety of CA3 inputs to trigger epileptiform activity. 4. Bath-applied PTX, at concentrations of 50-200 μM, had no apparent effect on the resting membrane potential or input resistance of the CA3 cells tested. Depolarizing current pulses elicited characteristic endogenous-burst responses that were not altered by PTX. 5. Synaptic activity evoked by mossy fiber stimulation was altered markedly by PTX. The pattern of observed changes indicated that PTX reduced inhibitory postsynaptic potential (IPSP) amplitudes, resulting in the appearance of repetitive (presumably recurrent) excitatory inputs. Paroxysmal depolarizing shifts (PDSs) were generated by the coalescence of these excitatory inputs. 6. Two types of spontaneous bursting were observed after PTX application. The first type was nonepileptiform, all or none in nature, and its frequency was voltage dependent. The second type of spontaneous burst was the PDS. It was epileptiform in character because it was associated with the synchronous discharge of many neurons. It was graded in nature, and its frequency was voltage independent. 7. The graded nature of the PDS was demonstrated by varying the duration and intensity of the orthodromic stimulation. Trains of stimulation could produce PDSs that lasted 500-800 ms. 8. A refractory period was observed following a PDS. By varying the strength of the orthodromic stimulation, it was possible to demonstrate that for the intervals tested this was a relative, not absolute, refractory period. 9. Intracellular recordings in CA3 neurons indicated that each spontaneous PDS was followed by an afterhyperpolarization (AHP). Analysis of quantitative measurements of AHP decay time and inter-PDS interval indicated that there was no significant correlation between these variables. 10. Hippocampal slices were divided surgically into two halves. One half consisted of isolated segments of CA2-3, whereas the other contained tissue from CA1 and dentate gyrus. After exposure to PTX but not penicillin, each isolated segment displayed spontaneous epileptiform discharges. Isolated as well as intact CA3 subfields displayed a marked periodicity in epileptiform discharge rate. In contrast, isolated CA1 regions had an aperiodic rate of significantly longer intervals between epileptiform events. 11. These experiments indicate that PDS generation results from the buildop of recurrent excitatory inputs. The important role of synaptic interactions in epileptogenesis is illustrated by the results with trains of stimuli. The pattern and number of recurrent excitatory connections and the relative balance of inhibition and excitation appear to be the important factors in determining the occurrence and nature of spontaneous epileptiform activity.