Reduction of external calcium and magnesium from 1.5 to 1.2 mM intensified potassium-induced interictal bursts, increased the likelihood of electrographic seizure occurrence in CA1, and rendered seizure initiation independent of N-methyl-D-aspartate (NMDA) receptor activation. In contrast to slices bathed in 1.5 mM divalent cations, in 1.2 mM divalents spontaneous CA1 seizures still occurred in CA1 minislices that contained at least 1500 neurons after removal of the CA3 burst generator, suggesting that divalent cations critically modulate the dependence of CA1 seizure initiation on interictal input. Since this slight reduction in external divalent cations enhanced tissue excitability, similar changes might promote epileptogenesis in situ.