Ten male patients with extensive primary endodermal sinus tumor of the mediastinum were treated with chemotherapy (with or without surgical excision and radiation therapy) between 1977 and 1985. Three patients, treated with cyclophosphamide-vincristine-based chemotherapy, died 1.5, 2.5, and 6.0 months, respectively, after initial diagnosis. Of the seven patients treated with cisplatin-based chemotherapy, one patient died of septicemia at 2.5 months after diagnosis and was disease-free at autopsy examination. Three other patients died of progressive disease at 7.0, 13.0, and 14.0 months, respectively. The three survivors remain alive at 17.0, 31.0, and 40.0 months from diagnosis; all are without evidence of disease. Of the three patients who underwent excision of the residual mediastinal tumor after cisplatin-based chemotherapy, persistent local disease was found in two patients. One of these two patients died of recurrent disease. All surviving patients had surgical resection of the tumor either before or after cisplatin-based chemotherapy, with or without radiotherapy and the timing of therapeutic interventions was guided by changes in the serum alpha-fetoprotein concentrations after initial therapy and during follow-up. Our experience suggests that the optimal management of patients with primary mediastinal endodermal sinus tumor requires an aggressive multidisciplinary approach guided by the extent of the tumor and the serum tumor marker levels.