Background Hepatic arterial infusion chemotherapy for liver metastases is under evaluation because of the high target dose and low general toxicity.To investigate the efficacy and safety of a Folfox4 regimen administered through a combined hepatic arterial and systemic infusion for the first-line treatment of colorectal cancer (CRC) with unresectable liver metastases.Methods Twenty-seven CRC patients with unresectable hepatic metastases and no prior chemotherapy were enrolled into the study They received a Folfox4 regimen; 1st day:HA(I) of oxaliplatin 85 mg/m2 and L-folinic acid 200 mg/m2,followed by a bolus hepatic arterial injection of 5-fluorouracil 400 mg/m2,then continuous HAl of 5-FU 600 mg/m2; 2nd day:infusion of L-folinic acid 200 mg/m2 i.v.followed by an intravenous bolus injection of 5-Fluorouracil 400 mg/m2,then　continuous infusion of 5-fluorouracil 600 mg/m2 i.v.The patients received HA(I) during the odd cycles,and the intravenous administration of the same Folfox4 regimen during the even cycles.Results A total of 236 treatment cycles were given with a median of 10 cycles.The therapy generated the following results after six treatment cycles:complete response (CR) 1/27 (3.7％),partial response (PR) 17/27 (63.0％),stable disease (SD) 6/27 (22.2％),and progress disease (PD) 3/27 (11.1％).Five patients had hepatectomy.The serum levels of both carcinoembryonic antigen (CEA) and CA19-9 were significantly reduced (P＜0.05).A median time to progression of 11 months and a median overall survival of 24 months were documented.The major adverse events included grade 1/2 nausea/vomiting,upper abdominal pain,peripheral neuropathy,and neutropenia/thrombocytopenia.Conclusions The Folfox4 regimen administered through combined hepatic arterial and systemic infusions is efficacious and safe for the treatment of CRC with unresectable liver metastases,and it facilitates the control of local lesions.