Anticonvulsant hypersensitivity syndrome is a disease characterized by multisystemic involvement, fever, lymphadenopathy, mucocutaneous rash, hypertransaminasemia and peripheral eosinophilia. This rare syndrome seems to be related to arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital and carbamazepine). Anticonvulsant hypersensitivity seems to be much more aggressive in patients undergoing concomitant radiotherapy. We report a case of anticonvulsant hypersensitivity syndrome developing toxic epidermal necrolysis with fatal outcome in a patient receiving cranial irradiation and aromatic anticonvulsants for seizure prophylaxis. This report attempts to emphasize the importance of an early diagnosis of this syndrome, the knowledge of the common cross-reactivity among the major anticonvulsants and the need for an appropriate measurement of the true benefits of seizure prophylaxis in patients with brain tumors.