A prospective, controlled randomized trial of hepatic arterial infusion of 5-fluorouracil (5-FU), adriamycin (ADM) and mitomycin C (MMC) [FAM group] versus 5-FU, epirubicin (EPIR) and MMC [FEM group] in patients with unresectable liver metastasis from colorectal cancer is reported. No objective response was observed in FAM group (n = 6), while two objective responses, 1 complete and 1 partial (22.2%), were achieved in FEM group (n = 9). There was no significant difference in the 50% survival period between the two groups (468 days in FAM group (n = 8) versus 462 days in FEM group (n = 10). Long survival over 2 years was observed in FEM group, but not in FAM group. Toxicities were recorded in 50% (3/6) of FAM group, and 80% (8/10) of FEM group, but they were mild and well tolerated. In conclusion, although there was no significant difference in clinical effects between the two groups, the use of EPIR instead of ADR in combination with 5-FU and MMC might be favorable for intrahepatic infusion chemotherapy because responders and long-term survival were exclusively observed in FEM group.