Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe life-threatening dermatologic conditions. To date, eight cases of TEN and one of SJS related to lamotrigine administration have been reported in the literature. Most patients were also taking concomitant valproic acid. It was hypothesized that valproic acid may interfere with glucuronidation of lamotrigine, leading to increased serum lamotrigine levels, or perhaps alter the drug's metabolism, resulting in accumulation of a toxic intermediate metabolite. Ultimately, this may possibly predispose a patient to increased dermatologic reactions, including TEN. A 54-year-old man developed TEN 4 weeks after beginning lamotrigine for complex partial seizures related to a glioblastoma multiforme brain tumor. The patient had also been taking concomitant allopurinol and captopril for more than 4 years with no complications, and valproic acid 3 months before the cutaneous event. Despite aggressive intensive care management, the patient died 17 days from the onset of symptoms due to multiple organ failure. Administration of lamotrigine, especially in combination with valproic acid, may lead to the development of TEN.