Weekly methotrexate may reduce valproate levels causing relapse of genetic generalized epilepsy.

•Seizures have been observed in epilepsy patients receiving high dose intravenous or intrathecal Methotrexate (Mtx) therapy for the treatment of leukemias, due to reduction in valproic acid (VPA) levels.•Prolonged low dose weekly Mtx exposure can also produce reduction in VPA levels causing seizure relapse as reported in this case.•Mtx competes with VPA for binding to albumin as a result of which a larger proportion of VPA become unbound and is rapidly metabolized by the liver causing decline in VPA levels.•Awareness about pharmacological interactions of anti-epileptic drugs (AEDs) is essential in epilepsy management.