BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown etiology characterized by a triad of symptoms: recurrent orofacial swelling, relapsing facial palsy. and a fissured tongue. A differential diagnosis must be made with other granulomatous diseases, such as sarcoidosis and oral Crohn disease; however, the histologic findings of noncaseating, sarcoidal granulomas support the diagnosis of MRS. RESULTS: Many therapeutic modalities have been described for this disease. In this case report, we present a patient with MRS that was treated with thalidomide because of the identification of tumor necrosis factor a in the lesion by immunohistochemical analysis. This is the first reported detection of tumor necrosis factor a in an MRS lesion, as well the first reported use of thalidomide to treat this clinical condition