The response of neocortical neurons to GABA is strongly influenced by the intracellular chloride concentration. We tested the hypothesis that activation of GABAA receptors can result in either depletion or accumulation of intracellular chloride. The measured reversal potentials of currents evoked by exogenously applied or synaptically released GABA were not significantly different. During GABA responses, voltage steps to the reversal potential revealed prominent tail-like currents. The polarity of these currents was opposite to that of the GABA-evoked currents, consistent with either accumulation or depletion of intracellular chloride. These results demonstrate that currents evoked by exogenously applied and synaptically released GABA share similar ionic dependencies. Current fluxes during GABAA receptor activation can be sufficiently large to change the intracellular chloride concentration. © 2001 Lippincott Williams & Wilkins.