BACKGROUND The anticonvulsant lamotrigine has been associated with severe adverse events such as the hypersensitivity syndrome and severe bullous reactions. So far, specific immunologic tests have rarely been performed to demonstrate specific sensitization. METHODS A 36-year-old man suffering from epilepsy was concomitantly treated with high doses of sodium valproate and lamotrigine. About 1 month later, a severe hypersensitivity syndrome occurred affecting skin, lymph nodes, and liver. Three months later, skin tests and lymphocyte stimulation tests with anticonvulsants were performed. RESULTS Skin tests were negative with all drugs; lymphocyte stimulation tests were twice positive with lamotrigine. Later re-exposure to sodium valproate was tolerated. CONCLUSIONS Lamotrigine may elicit a severe hypersensitivity syndrome. Particularly high initial doses and concomitant treatment with sodium valproate increase the risk of cutaneous reactions. The lymphocyte stimulation test was used to identify the culprit drug. Lymphocyte sensitization to the drug or a metabolite may be involved in the pathogenesis.