This phase II study examined bimonthly oxaliplatin (85 mg/m2) added to a continuous infusion of fluorouracil (3000 mg/m2 for 46 h following a 400 mg/m2 bolus), with leucovorin (LV) (150 mg/m2) administrated in a simplified way to patients with metastatic colorectal cancers (CRC) refractory or resistant to 5-fluorouracil (5-FU). Sixty patients were registered. Of the 52 evaluable patients, 3 (5.8%) achieved a complete response (CR) and 18 (34.6%) achieved a partial response (PR). The overall response rate (CR + PR) was 40.4% (95% confidence interval [CI]: 26.6%-54.2%) for evaluable patients and 35% (95% CI: 22.6%-47.4%) by intention to treat. The median progression-free survival (PFS) was 5.2 months, and the median survival was 14.2 months. No significant differences were seen in response rates and PFS of patient groups pretreated either with high-dose 5-FU/LV by continuous infusion or with intravenous 5-FU/LV by a weekly bolus. From the 421 cycles analyzed, dose-limiting toxicities included cumulative sensory neuropathy and leukopenia, accounting for 11.6% and 10.0%, National Cancer Institute-Common Toxicity Criteria grade 3/4 toxicities per patient, respectively. Two (3.3%) patients experienced hepatic encephalopathy related to high-dose 5-FU. With necessary caution, this regimen was effective for 5-FU-pretreated CRC, regardless of ethnic differences, and it had the advantage of LV being administrated at a low dose in a simplified way.