ObjectivePreceding oxygen glucose deprivation (OGD) and ongoing seizures have both been reported to increase neuronal chloride concentration ([Cl−]i), which may contribute to anticonvulsant failure by reversing the direction of chloride currents at inhibitory GABAA synapses.MethodsThe effects of OGD on [Cl−]i, seizure activity, and anticonvulsant efficacy were studied in a chronically epileptic in vitro preparation.ResultsSeizures initially increased during OGD, followed by suppression. On reperfusion, seizure frequency and [Cl−]i progressively increased, and phenobarbital efficacy was reduced. Bumetanide (10 μmol/L) and furosemide (1 mmol/L) prevented or reduced the OGD induced [Cl−]i increase. Phenobarbital efficacy was enhanced by bumetanide (10 μmol/L). Furosemide (1 mmol/L) suppressed recurrent seizures.Interpretation[Cl−]i increases after OGD and is associated with worsened seizure activity, reduced efficacy of GABAergic anticonvulsants, and amelioration by antagonists of secondary chloride transport.