Patients with advanced-stage unresectable hepatocellular carcinoma (HCC) were treated with intrahepatic arterial doxorubicin 30 mg/m2 plus escalating doses of cisplatin up to 100 mg/m2 in conjunction with rapid bolus injection of Spherex (degradable starch microspheres; Kabi Pharmacia, Lund, Sweden) into the hepatic artery, until slowing or reversal of blood flow. Treatments were repeated every 4 to 6 weeks until progression, or were continued indefinitely if there was disease stability or response. Thirty-five evaluable patients have so far been accrued to the study. Objective tumor responses have occurred in 22 patients (63%), of whom 20 had partial responses and two had complete responses. Four of the patients had reversal of tumor-induced portal vein thrombus. Toxicities included death, one patient (and a death of uncertain cause in an additional patient); hepatitis, two patients; pancreatitis, one patient; dyspnea/hypotension, two patients; and hepatic artery nontransient thrombosis in four patients. Six patients have survived 2 years and an additional 10 patients have survived 1 year. The addition of Spherex to intrahepatic arterial chemotherapy for advanced-stage HCC appears to be relatively safe and is well tolerated even in patients with portal vein thrombosis, which represent the majority of patients with advanced-stage HCC.