The outcome of systemic chemotherapy in metastatic hepatocellular carcinoma (HCC) patients had been disappointing. Based on the demonstrated antitumor activities and different mechanisms of action and toxicity profiles, we designed a phase II trial of combination therapy with doxorubicin and cisplatin in metastatic HCC patients anticipating a synergistic interaction of the combination. From January 1998 to January 2003, 42 consecutive patients with metastatic HCC were accrued. The regimen consisted of doxorubicin 60 mg/m2 delivered as an intravenous infusion over 30 min on day 1, followed by cisplatin 60 mg/m2 infused over 1 h on day 1. The cycle was repeated every 28 days. The objective tumor response was evaluated after two or three courses of chemotherapy. The serum alpha-fetoprotein level was measured at the start of every cycle. In total, 122 cycles of the regimen were administered, with a median of three cycles per patient (range one to eight cycles). The median age of the patients was 45 years (range 19–61 years), and 37 were evaluable for treatment response. The objective response rate was 18.9% (95% CI 8.0–35%) with one complete response and six partial responses. Six patients (16.2%) had stable disease and 24 patients (64.9%) had progression. Median overall survival of 37 patients was 7.3 months (95% CI 5.9–8.6 months). The median time to progression of all evaluable patients was 6.6 months (95% CI 5.4–7.8 months). Of 37 evaluable patients, 12 32.4%, 95% CI 18.0–49.8%) showed more than 50% decrease in AFP level from their baseline AFP and the median time to decrease in AFP by more than 50% was 1.8 months with a range of 0.7–4.7 months. The chemotherapy was well tolerated and the most common grade 3/4 side effects were neutropenia (14.3%), thrombocytopenia (11.9%), and diarrhea (9.5%). Combination chemotherapy with doxorubicin and cisplatin in metastatic HCC patients showed modest antitumor activity with relatively tolerable adverse effects. The objective response rate of the regimen was comparable to those found in other phase II trials, but the search for the optimal chemotherapy should be continued.