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Purpose Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m2, FU 400 mg/m2 IV bolus, FU 600 mg/m2 22-hour continuous infusion on days 1 and 2 every 2 weeks). Patients and Methods Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m2 HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. Results Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. Conclusion The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.