Epileptogenesis, i.e. the process leading to epilepsy with spontaneous recurrent seizures, can be initiated by a number of brain damaging insults, including traumatic brain injury, status epilepticus (SE), and stroke. Such acquired epilepsy is often associated with memory impairment and behavioral problems. There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection and prevention or modification of epileptogenesis induced by such brain insults. One promising candidate in this respect is valproic acid (VPA), a widely used AED that has been reported to exert neuroprotective activity in a number of in vitro and in vivo models. The present study investigated whether VPA reduces brain damage and improves functional outcome in a rat model of post-SE epilepsy. A self-sustaining SE was induced by prolonged electrical stimulation of the basal amygdala via a depth electrode. SE was terminated after 4h by diazepam, immediately followed by onset of treatment with VPA. VPA was injected i.p. at a bolus dose of 400mg/kg, followed by three times daily administration of 200mg/kg for 4weeks. A control group received vehicle instead of VPA after SE. Spontaneous seizures were recorded in all rats of both groups following termination of treatment, without significant inter-group difference in seizure frequency or severity. However, treatment with VPA after SE prevented the hyperexcitability and locomotor hyperactivity observed in vehicle-treated epileptic rats. Furthermore, VPA completely counteracted the neuronal damage in the hippocampal formation, including the dentate hilus. The data demonstrate that, although VPA does not prevent the occurrence of spontaneous seizures after SE, it exerts powerful neuroprotective effects and prevents part of the behavioral alterations, demonstrating that administration of VPA immediately after SE exerts a favorable effect on long-term functional outcome.