This phase II study was designed to evaluate the efficacy and toxicities of oral doxifluridine plus leucovorin as a randomized trial with those of intravenous 5-fluorouracil (5-FU) plus leucovorin in previously untreated metastatic colorectal cancer (CRC). Patients with metastatic CRC were randomized in either group A (oral doxifluridine 1,000 mg/m /d plus leucovorin 30 mg/d on days 1 to 7 and 15 to 21 of each cycle), or group B (intravenous 5-FU 400 mg/m /d plus leucovorin 20 mg/m /d on days 1-5 of each cycle), with the cycles repeated every 4 weeks. Between July 1998 and May 2000, 77 patients were enrolled (38 in group A and 39 in group B). Response rates were 23.7% (95% CI, 11-42%) in group A, and 15.4% (95% CI, 0-25%) in group B on an intent-to-treat analysis. The median response durations of the two groups were similar with 5.6 months in group A and 5.5 months in group B. Progression-free survival and overall survival were 5.4 months and 14.9 months in group A; 4.7 months and 19.5 months in group B. Toxicities in both groups were generally mild and reversible. This study shows that a combination of oral doxifluridine plus leucovorin can be active and safe as a first-line treatment for patients with metastatic CRC.