Ehlers-Danlos syndrome (EDS) is a collection of inherited connective tissue disorders with at least 10 types, differentiated on clinical and genetic grounds. Malignancy has been described only rarely in association with the syndrome. Epithelioid hemangioendothelioma (EH) is a rare endothelial tumor, which displays clinical behavior intermediate between that of hemangioma and angiosarcoma. A case report of a 50-year-old man with type IV EDS who was extensively investigated for several years for multiple mediastinal nerve palsies and chest pain. Magnetic resonance imaging (MRI) demonstrated an anterior mediastinal mass, which at biopsy showed EH. Subsequent metastatic spread to liver and lungs is unique among reported cases of mediastinal EH. The patient experienced significant symptomatic improvement from external beam radiotherapy (RT) to the mediastinum. After metastatic disease developed, multiagent chemotherapy was administered, but without response. The literature is reviewed regarding treatment of EH and the potential problems associated with EDS. Although there appears to be no etiological association between EDS and EH, the connective tissue disease clearly contributed to a delay in diagnosis and raised concerns regarding RT tolerance. The potential predisposition to aggressive tumor invasion remains a possibility. In addition, mediastinal EH has the potential to metastasize, and in this case demonstrated resistance to a broad range of chemotherapy agents.