Objective: To describe two identical cases of severe sodium valproate overdose treated with two different approaches. Design: Case report and review of the literature. Patients: Two cases of identical life-threatening valproate (VPA) overdose with high VPA blood levels, markedly elevated ammonia levels and coma. Interventions: One patient was treated with supportive therapy alone until the development of cerebral edema and seizures; the other was treated with immediate extended hemodialysis followed by high-volume hemodiafiltration. Measurements and main results: The first patient remained critically ill with elevated VPA and ammonia levels until the development of seizures and life-threatening cerebral edema. After the delayed application of hemofiltration, the patient slowly recovered to be discharged from intensive care on day 11. In contrast, the second patient's VPA and ammonia levels rapidly declined with hemodialysis and hemodiafiltration with rapid clinical improvement and intensive care discharge on day 3. Conclusions: In severe VPA overdose, early intervention with blood purification of suitable intensity was associated with a rapid reduction in VPA and ammonia levels and clinical improvement. This improvement was not seen with supportive therapy alone.