OBJECTIVE In this study, we explore the antiepileptic effects of flufenamic acid (FFA) in order to identify the cellular mechanisms that underlie the potential anticonvulsant properties of this nonsteroidal antiinflammatory compound. METHODS The mechanisms of FFA action were analyzed using an in vitro model in which epileptiform activity was induced in hippocampal slices by perfusion with 100 microm 4-aminopyridine (4-AP) added to a modified Mg(2+)-free solution. The activity of CA1 pyramidal neurons as well as the synaptic connection between CA3 and CA1 was monitored using extracellular and patch-clamp recordings. RESULTS Epileptiform activity was suppressed in hippocampal neurons by FFA at concentrations between 50 and 200 microm. Glutamatergic excitatory synaptic transmission was diminished by FFA without modifying recurrent gamma-aminobutyric acid (GABA)ergic synaptic inhibition. Several lines of evidence indicated that FFA did not decrease neurotransmitter release probability, implicating a postsynaptic mechanism of action. FFA also potently reduced neuronal excitability, but did not alter the amplitude, duration, or undershoot of action potentials. CONCLUSIONS Our results suggest that FFA exerts an anticonvulsive effect on hippocampal pyramidal neurons by simultaneously decreasing glutamatergic excitatory synaptic activity and reducing neuronal excitability. Therefore, our study provides experimental evidence that FFA may represent an effective pharmacologic agent in the treatment of epilepsy in the mammalian central nervous system.