One hundred and sixty-five patients with advanced colorectal cancer were entered into a prospectively randomized trial of combination chemotherapy comparing three 5-fluorouracil plus methyl CCNU (FM)-based regimens: FM plus ICRF-159 (FMI), FM plus triazinate (FMT), and FM plus vincristine (FMV). Patients were stratified according to performance status, anatomic site of primary indicator lesion, and prior chemotherapy. Those with abnormal kidney or liver function were randomized between FMI and FMV because triazinate depends on both hepatic and renal mechanisms for elimination. There were no significant differences between the treatment regimens in objective response rate (11%-17%), interval to progression (median, 10-14 weeks), or survival (median, 5-6 months). The primary side effect observed was hematologic toxicity, which tended to increase in severity with repeated courses of therapy. Although ICRF-159 and triazinate have been shown to have limited single-agent phase II activity against colorectal cancer in previous trials, neither agent combined with 5-fluorouracil plus methyl CCNU has an improved treatment effect compared with FMV. We do not recommend the further use of these regimens in the treatment of advanced colorectal cancer.