FOURTEEN PATIENTS with metastatic adenocarcinoma of unknown primary origin were treated initially with a chemotherapeutic regimen combining cyclophosphamide, adriamycin, and 5-fluorouracil (CAF). Two patients (14%) obtained objective response to CAF and an additional patient responded to vinblastine and bleomycin following CAF failure. Median survivial in the group as a whole was 7+ months. However, patients who benefited from chemotherapy survived a median of 15+ months. While objective response rate with CAF is no greater than that reported with other regimens, median survival may be prolonged. As there was no severe drug-related toxicity using the CAF combination, it is a reasonable approach to initial therapy in adenocarcinoma of unknown origin.