A phase II trial of 5FU in modulation with intravenous high-dose levofolinic acid and oral hydroxyurea (HU) in advanced unresectable hepatocellular carcinoma (HCC). A total of 50 consecutive patients, 38 males (76%) and 12 females (24%), with a mean age of 62 years (range 30-74) and a mean performance status of 80 (KI, range 60-90) were enrolled. The vast majority of patients were therapy-naive, although two patients (4%) had previous surgery and showed progressive disease at entry. No patient had been previously treated with chemotherapy. Five patients had previous hormonotherapy with tamoxifen. Most patients had disease limited to the liver while 12 patients (24%) had also metastatic deposits outside the liver. The treatment plan included: levofolinic acid 100 mg/m2 diluted in 500 cc of normal saline over 2 hour infusion followed by 5FU 600 mg/m2 i.v. bolus. HU 1,000 mg/m2 was given by mouth in three refracted doses starting 6 hours after 5FU. A PR was recorded in only 5 patients (10%; 95% CL 1%-34%) with a median duration of 5.7+ months (range 4.0/6.2 months), a stabilization in 15 (30%) with a median duration of 3.8 months, while 30 patients progressed (60%). PR were seen at liver primary tumor in 4 cases and at soft tissue in 1 case. The median survival was 5.8 months (range 2.0/12.0+). The most frequent toxicities were leukopenia (32%), which however was mild (grade 1-2) in all cases, and grade 1-2 thrombocytopenia observed in 15% of cases. Mild grade 1-2 vomiting was recorded in one third of patients, and grade 1-2 stomatitis in 15%. The combination of 5FU with levofolinic acid and oral HU on a weekly schedule is largely inactive against unresectable or metastatic HCC and results are no better than historical data reported for 5FU alone.