During and after intense neuronal activity the concentration of extracellular potassium ([K+]o) increases while the concentration of calcium ([Ca2+]o) decreases. The present study examined the effect of increased [K+]o alone, and with a parallel decrease in [Ca2+]o, on overall excitability, long-term potentiation (LTP), and the appearance of epileptiform discharges. [K+]o and [Ca2+]o were varied over the range in which they fluctuate in vivo. Hippocampal slices were first equilibrated in a control artificial CSF containing 3.1 mM K+ and 1.5 mM Ca2+ and then reequilibrated in an identical solution except that the K+ was increased to 3.55, 4, 5, 6, or 8 mM with and without a decrease in Ca2+ to 1.0 mM. Raising [K+]o caused a leftward shift of input-output curves. Lowering [Ca2+]o to 1.0 mM had no effect on the ability of [K+]o to shift the input-output curve to the left. LTP was not changed by increasing [K+]o. Lowering [Ca2+]o to 1.0 mM blocked LTP and increasing the [K+]o did not overcome this blockade. When [K+]o alone was altered, the [K+]oS at which epileptiform bursts occurred 50% of the time were 5.6 and 7.6 mM for stimulus-locked and spontaneous bursting, respectively. The combination of decreased [Ca2+]o and increased [K+]o made slices considerably more prone to epileptiform activity. In 1.0 mM [Ca2+]o, the [K+]o at which 50% of the slices showed stimulus-locked bursting was decreased to 3.6 mM while that for spontaneous discharges was 5.4 mM. The sensitivity of hippocampal slices to [K+]o and [Ca2+]o, and the synergistic actions of alterations of these ions, indicates that even small changes in the aggregate extracellular ionic milieu may be important in epileptogenesis.