Toxic epidermal necrolysis (TEN) is a severe mucocutaneous syndrome that can be occasionally caused by anticonvulsant drugs. In some cases, cranial irradiation may act as a precipitating factor. Thus, in cancer patients who suffer from brain metastases and are administered antiepileptic drugs for seizure prophylaxis, the risk of developing TEN after receiving palliative brain radiotherapy cannot be ignored. We is reported. The case of a young patient with non-small cell lung cancer (NSCLC) treated with prophylactic phenobarbital who developed TEN within a few days of completing cranial radiotherapy for brain metastases is reported. To minimize the risk of TEN in patients undergoing brain radiotherapy, prophylactic anticonvulsant therapy is recommended only after an accurate measurement of the true benefits. Alternatively, discontinuation of antiepileptic treatment before the initiation of brain radiotherapy, or the use of anticonvulsants associated with a lower risk of developing cutaneous reactions might be considered.