In cortical neurones, E_GABA is governed by a low intracellular chloride, maintained by a K⁺-coupled outward transport for Cl^– (Thompson et al. 1988), and the bicarbonate gradient (Kaila et al. 1993). Neurones in slices from human epileptogenic tissues, however, exhibit a depolarising GABA_A inhibition (Deisz et al., 1998, Cohen et al. 2002). We further evaluated these depolarising GABA_A responses and the underlying mechanisms. Layer 2/3 neurons were investigated in slices of human cortical tissues from epilepsy surgery with sharp microelectrode recordings (for methods see Deisz, 1999). Kinetics of anion transport mechanisms, were evaluated by monitoring the IPSP_A amplitudes before, during and after injections of anions. IPSP_A were pharmacologically isolated by ACSF containing 10µM CNQX, 20µM D-APV and 2µM CGP55845A (CDC-ACSF). With K-acetate filled electrodes, the reversal potentials of the composite EPSP and IPSP response of human neurones averaged -54.2±10.6mV (mean±s.d.; E_m:-71.5±4.8 mV, n=82) in control condition and -61.5±8.5mV (E_m:-71.4±6.5mV, n=46) in CDC-ACSF. Of these 46 neurones, 20 had an E_IPSP more negative than -65mV, on average -69.5±2.7mV, whereas the E_IPSP of the other 26 averaged -56.5±5.7mV (P<0.001, t- test). After current injection from KCl-filled electrodes, the IPSP_A recovered with a time constant (τ) of 18.3±5.9s in CDC-ACSF (n=17), close to control values (21.5±8.4s, n=24; P=0.24) in ACSF. Only two neurones exhibited a τ below 10s. Bath application of furosemide (200µM) in CDC-ACSF reversibly increased the amplitudes of IPSP_A (from 7.9 ±5.1mV to 11.6±7.9 mV, n=5, P=0.034) and increased τ of recovery from 16.3±7.5s to 44.3±9.5s (n=5, P=0.002). Application of bumetanide (50µM) had no effect on the amplitudes of isolated IPSP_A (control: 6.3±4.5mV, bumetanide: 6.6±4.9mV; n=6, P>0.5) and increased the τ of recovery from 19.4±4.4s to 25.7±1.5s (n=5; P=0.017). The τ after injection of nitrate (not carried by KCC2) averaged 34.9±11.2s (n=4. Preliminary experiments using reduction of K⁺_o from 5 to 2.5mM had no effect on τ of recovery. To validate our methods, we evaluated the kinetics of Cl^– extrusion also in rat cortical neurones. The t from Cl^– injection averaged 8.7±3.0s (n=17) in CDC-ACSF. Bumetanide and furosemide increased τ from 6.9±1.2s to 9.3±2.4s (n=7; P=0.036) and from 6.6±1.3s to 14.1±1.3s (n=3), respectively. Preliminary data from rat neurones indicate that reduction of K⁺_o decreased τ of recovery from about 10s to 7s. The data indicate an impaired Cl^– extrusion in some human cortical neurones from epileptogenic tissues. The reduced Cl^– extrusion may contribute to elevated Cl^–_i, particularly by synaptic Cl^– fluxes. It remains to be determined whether impairments of Cl^– homeostasis relate to the severity of epilepsy.