The role of etoposide in the treatment of poorly differentiated carcinoma of unknown primary site. Patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA) of unknown primary site comprise 25% to 35% of the patients with carcinoma of unknown primary site. Some of these patients have neoplasms that are highly responsive to combination chemotherapy, and a minority have potentially curable tumors. Between 1978 and 1982, 68 patients were treated with combination chemotherapy (most received cisplatin, vinblastine, and bleomycin [PVB] with or without doxorubicin). Thirty-eight patients (56%) responded to treatment, with 15 (22%) complete responder (CR) and 9 (13%) long-term, disease-free survivors. Since that time, we have incorporated etoposide into the treatment of these patients because of its synergism with cisplatin and its great activity against several other neoplasms, including germ cell tumors. Seventeen patients with PDC of unknown primary site received salvage therapy with etoposide and cisplatin after failing PVB. Ten of these patients had partial responses (PR), with a median response duration of 5 months (range, 2 to 12 months). Thirty-two previously untreated patients with PDC received etoposide and cisplatin combinations as initial treatment. Eighteen of 30 evaluable patients (60%) responded to therapy, and 11 patients (37%) had CR. Seven patients remain disease-free 39 to 63 months after the completion of therapy. Etoposide is an active drug in the treatment of PDC of unknown primary site. Preliminary results indicate that initial treatment with etoposide and cisplatin combinations produces results equivalent to or superior to those achieved with PVB. 