Between October, 1986, and March, 1990, 20 consecutive untreated and noncirrhotic patients with measurable and histologically and/or cytologically confirmed unresectable primary liver cancer were randomly assigned to intravenous (10 patients) or intra-arterial (10 patients) therapy. Patients were treated every 4 weeks with a combination chemotherapy regimen containing 4' epidoxorubicin and 5-fluorouracil. A 3-min bolus injection of 4' epidoxorubicin was followed by 5-fluorouracil given in a 90-min infusion. The dose of 4' epidoxorubicin was escalated: the starting dose was 40 mg/m2, the second dose was 50 mg/m2, and thereafter 60 mg/m2 during subsequent cycles. The dose of 5-fluorouracil was always 800 mg/m2. Objective response rates (20%) were similar in both treatments; two patients had partial responses in the intra-arterially treated group and one complete and one partial response were recorded in the intravenously treated group. The median survival time was 15.2 months for the patients treated intra-arterially and 13.8 months for the patients treated intravenously. Toxicity was mainly mild in both groups with less hematopoietic toxicity in the I.A.-treated group. 4' epidoxorubicin combined with 5-fluorouracil given intra-arterially is not superior to the intravenous therapy, but it may diminish systemic toxicity.