PURPOSE: The aim of this study was to analyze the impact of hepatic arterial infusion (HAI) of oxaliplatin with systemic 5-Fluorouracil and leucovorin on patients with isolated unresectable liver metastases. PATIENTS AND METHODS: A total of 87 patients treated in our hospital with HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin for isolated unresectable colorectal liver metastases from May 1999 to May 2007 were extracted from a prospective database and analyzed. The resectability rate, perioperative findings, postoperative outcomes, and long-term follow-up were evaluated. RESULTS: HAI was delivered after failure of previous systemic chemotherapy in 69 patients (79%). The main criterion for unresectability was massive liver involvement (86% of patients). Most patients had synchronous (85%), bilateral metastases (89%). The median number of HAI courses was 8 (0-25). About 31 patients experienced technical catheter-related problems, which were responsible for withdrawal of HAI in only 7 patients (8%). Finally, a total of 23 patients (26%) were operated on, and resection or radiofrequency ablation was performed in 21 patients (24%). No postoperative mortality was observed and the morbidity rate was 35%. Five-year overall survival was 56% in the surgery group versus none in the nonsurgery group (P < 0.0001). After a median follow-up of 63 months, intrahepatic recurrence occurred in 10 patients among the 23 operated patients. CONCLUSIONS: HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin offers a second chance to remove initially unresectable isolated colorectal liver metastases in 24% of patients, and appears to be more efficient when performed as first-line therapy. Long-term overall survival can be obtained with this approach.