Nefopam is a centrally acting, non-opiate analgesic drug used in the prevention of post-operative pain. In this study, the effect of nefopam on epileptic seizures and neuronal brain damage induced in the rat by pentylenetetrazole (PTZ) was examined. Status epilepticus was induced by repeated injections of PTZ and rats were treated with nefopam at 20 or 40 mg/kg, phenytoin at 30 mg/kg or both nefopam 40 mg/kg and phenytoin. Seizure scores, the latency and threshold dose of PTZ for status epilepticus were determined. Brain malondialdehyde, reduced glutathione, nitric oxide, and paraoxonase-1 activity were measured and histological study done. Results showed that the increase in malondialdehyde and nitric oxide levels and the decrease in reduced glutathione content and paraoxonase-1 activity caused by PTZ in the rat brain were significantly ameliorated by treatment with nefopam and nefopam/phenytoin. The mean epilepsy scores were significantly decreased, while the latency and threshold dose of PTZ for developing status epilepticus significantly increased by nefopam, phenytoin or their combination. Additionally, nefopam had no significant effect on the anti-convulsive action of standard antiepileptic drug phenytoin. The histological study demonstrated that the neurodegenerative changes induced by PTZ, namely, the dark shrunken cortical and hippocampal neurons were ameliorated by 40 mg/kg nefopam or nefopam/phenytoin administration. These data suggest that in experimentally-induced status epilepticus, nefopam decreases oxidative stress, exerts anticonvulsant and neuroprotective effects without influencing that of phenytoin. Nefopam, therefore, could be of value as an adjunct to phenytoin in the treatment of epilepsy in humans.