Background: The aim of this study was to evaluate the therapeutic efficacy and safety of hepatic arterial infusion (HAI) with irinotecan, oxaliplatin, and floxuridine as a first-line treatment in patients with unresectable liver metastases of colorectal cancer (CRC). Patients and Methods: Individual patients were treated with irinotecan (120 mg/m(2)), oxaliplatin (100 mg/m2), and floxuridine (500 mg/m2) via tumor-supplying arteries. Intravenous leucovorin (200 mg/day) and floxuridine (300 mg/m(2)/day) were given on days 1-3 after the procedure. The therapeutic courses were repeated every 4-8 weeks. Tumor responses, overall survival, and the time to tumor progression were observed. Results: 204 cumulative cycles of chemotherapy were performed for 31 patients (median 7.0). 19 patients achieved a partial response; in 10 patients the disease stabilized, and in 2 patients the disease progressed, producing an overall response rate of 61.3%. The median survival time was 24.8 months, and the median time to tumor progression was 10.1 months. Frequencies of grade 3-4 neutropenia, diarrhea, elevation of serum bilirubin, elevation of serum transaminases, and vomiting were 6.5, 9.7, 3.2, 19.4, and 90.3%, respectively. Conclusion: This triple-combination chemotherapy as first-line treatment through HAI was well tolerated and effective in patients with unresectable liver metastases of CRC.