To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV). Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days. There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump. HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.