BACKGROUND Extragonadal germ cell tumors (EGGCT) are uncommon, occur primarily in the mediastinum and retroperitoneum, and have been noted to have variable response rates to cisplatin-based chemotherapy regimens. METHODS The Southwest Oncology Group (SWOG) has completed a prospective trial of combination chemotherapy followed by surgical removal of residual disease in patients with this type of germ cell neoplasm. Chemotherapy consisted of alternating cycles of vinblastine, bleomycin, and cisplatin with etoposide, bleomycin, doxorubicin, and cisplatin. Four cycles of therapy were given followed by surgical removal of residual disease where appropriate. RESULTS Fifty patients were entered into the trial, and 41 were eligible, with 4 patients excluded by pathology review. Of the 41 eligible patients, 24 had mediastinal tumors, 15 had retroperitoneal tumors, and 2 had unknown primary sites. Complete response rates (chemotherapy +/- surgery) for the various sites were as follows: mediastinum, 18 of 24 (75%); retroperitoneum, 10 of 15 (67%); and unknown primary, 2 of 2 (100%). At 2 years, the disease-free survival rate for all patients was 87%. At a median follow-up of 6.8 years, 26 of 41 patients (63%) are alive. The toxicity of the chemotherapy regimen was substantial, with neutropenic fever developing in 17 of 41 patients (41%) during treatment. Additional side effects included nausea and vomiting (76%), mucositis (27%), and pulmonary toxicity (5%). CONCLUSIONS This prospective trial of chemotherapy in patients with EGGCT demonstrates a significant response in patients with either mediastinal or retroperitoneal tumors and a 4-year survival rate of more than 60% and 70%, respectively.