The effect on interictal EEG epileptic activity (IEA) of oral flumazenil, a benzodiazepine antagonist and potential antiepileptic drug, was studied in 12 adults with refractory epilepsy. Comparisons were made with placebo and 15 mg diazepam using a double-blind, randomised, cross-over design. A significant reduction in IEA from the baseline epileptic discharges was observed after flumazenil administration (at a dose of 30 or 100 mg) with a low incidence of adverse events. In patients who achieved > 50% reduction in the frequency of IEA, the median duration and extent of action of flumazenil (at either dose) were greater than for diazepam 15 mg or placebo. The frequency of response and duration of action with oral flumazenil were comparable to those obtained via the intravenous route. These results suggest that oral flumazenil may have an intrinsic antiepileptic activity and provide a rationale for a new approach in the treatment of intractable epilepsy.