The relation between interictal bursts (IIBs) and seizures in epilepsy is obscure. Results from some human and animal studies suggest that IIBs may actually suppress seizure activity. This appears particularly true in the zero magnesium in vitro seizure model. Here we provide new evidence in support of this and new insight into the mechanisms of seizure suppression in this model. Brain slices containing hippocampus and entorhinal cortex were bathed in zero magnesium medium. Electrographic seizures appeared, then were replaced by IIBs. Upon lowering [K+]o and raising [Ca2+]o the IIBs disappeared and the seizures reappeared. Repeated stimuli mimicking IIBs then suppressed seizures again. Selective knife cuts revealed that the IIBs originated in the hippocampus (area CA3) whereas the seizures originated in entorhinal cortex. These results confirm that IIBs suppress seizures in the zero magnesium model. They also show that an important aspect of the interaction between IIBs and seizures in this model is the anatomical segregation of their respective sites of origin. This may apply in other models and in human epilepsy as well. Finally, these results illustrate that one consequence of the anatomical segregation and mutual interaction of IIBs and seizures is that influences which are locally pro- or antiepileptic can have opposite effects in a broader region.