Background: Febrile infection-related epilepsy syndrome (FIRES) is a devastating entity characterized by acute onset of refractory epileptic status preceded by a febrile infection, for which no aetiology has been identified so far. Methods: We report the cases of two males presenting with typical FIRES, for whom extensive investigations revealed no specific aetiology. Failure of controlling seizures with multiple anticonvulsants as well as barbiturate coma lead to the decision to try immunotherapy. The first patient received plasma exchange after a negative trial of IVIGs, while the second received plasma exchange in the beginning. Results: Significant improvement in the seizure frequency and intensity was obtained following plasma exchange, and weaning of barbiturate coma was successful in the days following treatment. Both patients remain with significant temporal lobe epilepsy, requiring treatment with 3 anti epileptics. However, cognitive outcome is surprisingly good for both, both exhibiting normal IQs and normal everyday function, with the second patient showing even better recovery, possibly due to earlier treatment with plasma exchange. Conclusion: Our findings of favourable outcome with plasma exchange favours the auto-immune hypothesis often discussed in FIRES. While awaiting further insight onto the aetiology of this syndrome, we suggest a trial of plasma exchange in patients affected.