Prognosis of advanced hepatocellular carcinoma is dismal when locoregional treatments have failed. Systemic chemotherapy is seldom effective in inducing objective response and prolonging survival. We report a case of complete pathological remission of hepatocellular carcinoma after three cycles of systemic chemotherapy. A 64-year-old woman presented with histologically documented hepatocellular carcinoma without associated liver disease, relapsed after earlier locoregional therapy. Surgery was not performed as thoracic computerized tomography (CT) demonstrated pulmonary bilateral nodules. The patient was treated with chemotherapy consisting of three cycles of epirubicin, cisplatin, and infusional 5-fluorouracil (ECF regimen); stable lung disease and a good partial response in the liver were obtained as documented by CT scan. Hepatic segmentectomy was therefore performed and the histologic examination revealed necrosis without evidence of residual disease. Two more cycles of adjuvant chemotherapy were infused after surgery. At 1-year follow-up the patient is alive and free of disease according to a positron emission tomography/CT scan. It is suggested that an aggressive regimen like ECF should be considered in fit patients who are not affected by concomitant liver disease.