A total of 26 patients with advanced colorectal cancer received 60 mg/m² methotrexate i. v. on days 1 – 4; 400 mg/m² 5-fluorouracil i. v. on days 2, 3, 5, and 6; and 100 mg/m² 6S-leucovorin i. v. on days 2, 3, 5, and 6. Interferon-α2b at a dose of 3 million U was given i. m. daily for the 6 days of chemotherapy. Courses were repeated every 3 weeks. There were four partial responses for a response rate of 15% (95% confidence interval 2 – 28%). In all, 14 patients expressed grade 3 toxicity; 9 patients had diarrhea, 3 had stomatitis, and 2 developed leukopenia. In conclusion, multimodal biochemical modulation of 5-fluorouracil, at least on this schedule, does not seem to be effective, as it results in severe toxicity.