Between 1978 and 1990, 173 patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site were treated with bleomycin-containing regimens at Vanderbilt University Medical Center. Patients were prospectively identified based on light microscopy findings. The median age of patients was 39 years; 78% were male and 76% had metastatic tumors in two or more sites. Dominant tumor location was the mediastinum, retroperitoneum, or peripheral lymph nodes in 82 patients (47%). Between 1978 and 1985, patients received cisplatin 20 mg/m2 intravenously (IV) days 1 through 5, vinblastine 0.15 mg/kg IV days 1 and 2, and bleomycin 30 U IV weekly. In 1986, etoposide 100 mg/m2 IV days 1 through 5 replaced vinblastine in the regimen. Responding patients received four courses of therapy at 3-week intervals. One hundred thirteen patients (65%) had a major response to therapy, including 47 (27%) complete responses. At present, 27 patients are disease free at a median of 78 months posttherapy (range, 11 to 142 months); an additional patient was lost to follow-up while in complete response. Median survival of the entire group was 11 months, with a 12-year actuarial disease-free survival of 16%. Combination chemotherapy with cisplatin/bleomycin and either vinblastine or etoposide is highly active in patients with poorly differentiated carcinoma of unknown primary site and is curative in a minority of these patients. A trial of this therapy should be considered in all such patients.