We used the patch clamp technique in whole-cell configuration to investigate the membrane current and membrane resistance of neurons in rat hippocampal tissue slices during spreading depression (SD) induced by high K+ solution or electrical stimulation and during SD-like depolarization caused by hypoxia. The potential of the patch pipette was referred to an extracellular micropipette electrode to ensure control of the true membrane potential during large shifts of extracellular potential, delta Vo. During both hypoxic and normoxic SD, increase of holding current indicated a large inward current which reached a mean maximum of about 1.75 nA. This virtual inward current started and ended at the same time as the extracellularly recorded negative delta Vo shift, but the trajectories of the two differed. When the membrane was clamped at strongly positive potential, the current during SD was outward. The average apparent reversal potential of the current during SD was near zero but in individual cases varied from -26 mV to + 12 mV. During SD the input resistance decreased on the average to 43% of the resting control value. The decrease of the input resistance was not voltage dependent. The increase of holding current and decrease of resistance occurred with both Cs- and K-gluconate recording pipettes and was not suppressed by 2 mM intracellular QX-314. Voltage-gated currents disappeared during SD; a small, Cs(+)-resistant outward rectifying current was the last to be lost. During recovery, reversal potential and input resistant overshot the control level and then returned to normal within about 5 min. The data are consistent with change of both driving potential and conductance for several ions, but the decrease of overall membrane resistance was less than earlier estimates with other methods had suggested. Normoxic SD and hypoxic SD-like depolarization could not be distinguished by these tests.