Sudden unexpected death in epilepsy (SUDEP) is a dramatic outcome for epileptic patients, with a prevalence of 1 per 1000. Stiripentol (STP, Diacomit©) is an antiseizure medication indicated for Dravet syndrome, a rare developmental and epileptic encephalopathy with high mortality rate (15 per 1000), in which SUDEP accounts for about 2/3. Here, we evaluate the effects of STP on seizures and death using audiogenic seizure in a preclinical model of SUDEP.In the DBA/2 SUDEP model, audiogenic seizures were induced, and different concentrations of STP were tested at various timings between administration and stimulation on seizure severity and respiratory arrest induced death. Tissue levels of STP were measured by UV-HPLC to evaluate its effective concentrations against seizures and SUDEP.STP prevented tonic-clonic seizures and associated death in a dose-proportional manner, when audiogenic seizures were induced 30 min after STP systemic administration. At the optimal concentration (75 mg/kg), STP prevented tonic seizures between 30 min and 4h and prevented death up to 2h. The efficacy of STP was associated with high brain levels at 1h.In addition to its antiseizure effects, STP has a potent impact against epilepsy-related death, evaluated here in a preclinical model of SUDEP. In Dravet syndrome, the effect of STP on SUDEP rates is not described. The present results suggest that STP has direct pharmacodynamic protective effects in DBA/2 mice. Future studies will evaluate the mechanisms of action of STP sustaining its effects against epilepsy-related mortality.