The combination of 5-fluorouracil (5-FU) plus leucovorin (LV) with oxaliplatin has become one of the standard treatments for advanced colorectal cancer (CRC). Two consecutive phase II trials assessed the efficacy and safety of combined therapy with oxaliplatin and high-dose 5-FU without LV for patients with advanced CRC. A total of 89 patients were enrolled in both trials. Fifty-nine patients in trial A underwent a scheduled regimen of biweekly oxaliplatin 85 mg/m(2) and weekly nonmodulated 5-FU 3.0 g/m(2). Increased incidence of toxicity led to a 25% reduction in the starting dose of 5-FU (2.25 g/m(2)) for trial B. Patients treated in trial B showed a higher cumulative dose and relative dose intensity for oxaliplatin and 5-FU than those treated in trial A. Response to treatment, time to progression (TTP), overall survival (OS), and duration of response were evaluated as efficacy variables. Overall response rate was preserved despite the reduction in 5-FU dose (55.9% and 63.0%, respectively). Median durations of responses were 10.6 and 10.4 months, median TTPs were 7.7 and 7.3 months, and OS times were 21.7 and 13.1 months, respectively. Reduction in the starting 5-FU dose from 3.0 to 2.25 g/m(2) resulted in a decrease in the main grade 3/4 hematologic toxicities (neutropenia, 22.0% to 10.0%) and nonhematologic toxicities (diarrhea, 52.5% to 23.3%; nausea/vomiting, 18.6% to 3.3%). Neurosensory toxicity was similar in both trials (16.9% and 16.7%). Biweekly oxaliplatin in combination with nonmodulated high-dose 5-FU is an active, well-tolerated treatment that offers a lower cost than a modulated schedule for patients with advanced, metastatic CRC.