1. Sinusoidal high frequency (20-50 Hz) electric fields induced across rat hippocampal slices were found to suppress zero-Ca2+, low-Ca2+, picrotoxin, and high-K+ epileptiform activity for the duration of the stimulus and for up to several minutes following the stimulus. 2. Suppression of spontaneous activity by high frequency stimulation was found to be frequency (< 500 Hz) but not orientation or waveform dependent. 3. Potassium-sensitive microelectrodes showed that block of epileptiform activity was always coincident with a stimulus-induced rise in extracellular potassium concentration during stimulation. Post-stimulus inhibition was always associated with a decrease in extracellular potassium activity below baseline levels. 4. Intracellular recordings and optical imaging with voltage-sensitive dyes showed that during suppression neurons were depolarized yet did not fire action potentials. 5. Direct injection of sinusoidal current into individual pyramidal cells did not result in a tonic depolarization. Injection of large direct current (DC) depolarized neurons and suppressed action potential generation. 6. These findings suggest that high frequency stimulation suppresses epileptiform activity by inducing potassium efflux and depolarization block.