BACKGROUND Hepatic arterial infusion of zinostatin stimalamer and lipiodol emulsion shows a moderate activity against hepatocellular carcinoma. However, the anti-tumor activity of zinostatin stimalamer alone is uncertain. METHODS The primary endpoint was to evaluate the frequency of dose-limiting toxicity and determine the maximum-tolerated dose of zinostatin stimalamer when used by intra-arterial infusion. The candidates for this study were patients with hepatocellular carcinoma no longer amenable to established forms of treatment. Hepatic arterial infusion chemotherapy was performed by selectively introducing a catheter into the hepatic artery with zinostatin stimalamer alone. Treatment was repeated at 4-8-week intervals until disease progression or the appearance of unacceptable toxicity. The starting dose of zinostatin stimalamer was 3 mg/m(2), and doses were increased in 1 mg/m(2) increments in successive cohorts. At least three patients were treated at each dose level and three additional patients were treated in the presence of dose-limiting toxicity. RESULTS Twelve patients were entered into this trial. Dose-limiting toxicity was observed in one of six patients at 3 mg/m(2), and in two of six patients at 4 mg/m(2). The maximum-tolerated dose was judged to be 3 mg/m(2) with liver dysfunction and serum creatinine increase as the dose-limiting toxicity. There was one early death suggested to be related to the protocol treatment. None of the 12 patients achieved an objective tumor response. CONCLUSIONS Hepatic arterial infusion with a zinostatin stimalamer of 3 mg/m(2) may be tolerated, but not active, in patients with far advanced hepatocellular carcinoma.