Tuberous sclerosis is an autosomal dominant genetic disorder that is characterized by the early development of hamartomas, malformations, and congenital tumors of the nervous system, skin, kidneys, lungs, and heart. Variable clinical expressivity has been reported and more than one gene can be responsible for the disorder. Benign neoplasias accompanying the syndrome are common but malignant neoplasias are rare, being generally mesenchymal and possibly affecting the jaws. We report here a clinical case of a malignant fibrous histiocytoma (undifferentiated high-grade pleomorphic sarcoma) of the mandible in a patient with tuberous sclerosis.