In this retrospective study, 91 patients (30%) out of a series of 304 with metastatic cancer of unknown primary site were found to have liver metastases. The liver was the only metastatic site in 28 (31%) cases and was associated with other sites in 63 (69%) cases. Median age was 62 yr in 61 male patients and 59 yr in 30 female patients. Thirty patients were submitted to an extensive investigation in search of the primary tumor, including systematic endoscopies: no primary cancer was found in these patients. In 61 other patients, only symptom-oriented investigations were performed and the primary cancer was found in 11 cases. The histologic type was adenocarcinoma in 71 (78%) cases, undifferentiated in 11 (12%) cases, epidermoid in 5 (6%) cases and determined by cytology alone in 4 cases. The median survival was 4 months in patients with metastases in the liver only, and 5 months in the other patients. This difference was not significant, so prognostic factors such as the Karnofsky index, weight loss, CEA and LDH levels were evaluated in the entire group; these factors do not have significant prognostic value. By contrast, when patients were able to receive chemotherapy, median survival was better (4 months) than without (median survival: 1 month; P = 0.005). In addition, in the case of objective response to chemotherapy, the median survival was 9 months versus 3.5 months for patients without objective response (P = 0.001). Seventy-three out of 91 patients (80%) were treated with chemotherapy regimen; 65 patients were evaluable: the objective response rate was 11 +/- 7% (7/65). Different regimens were used. With a non-toxic combination of fluorouracil, vinblastine and cyclophosphamide, 3 partial responses greater than or equal to 50% out of 43 patients (7 +/- 8%) were obtained. No significant advantage was observed when adriamycin was added to FU (4/13): 31 +/- 25%. Second- or third line chemotherapy regimen due to progression of the disease after the first-line combination provided only one objective response out of 36 patients. According to this retrospective study we recommend that overinvestigation be avoided in patients, with liver metastases of unknown primary site and that these patients be treated with non-toxic drug combinations.