In the United States and Europe, the combination of oral UFT plus leucovorin has been reported to produce objective responses and survival rates similar to those achieved with standard intravenous 5-fluorouracil plus leucovorin in patients with metastatic colorectal cancer, with reduced toxicity. However, because knowledge and experience with UFT plus leucovorin are relatively limited in Japan, we conducted a phase II study to evaluate the safety and efficacy of this combination in Japanese patients with metastatic colorectal cancer. For the purposes of this study, 20 patients received oral UFT 400 mg/m2/day in two divided doses (q 12 h) and a 5-mg tablet of leucovorin (q 8 h). Treatment was administered for 5 days, followed by a 2-day rest period, for a 28-day cycle. There were six partial responses (30%) and one complete response (5%) (overall response rate, 35%; 95% confidence interval, 14.1% to 55.9%). Greater efficacy of UFT plus leucovorin was demonstrated in patients with lung metastases, with a response rate of 63% (five of eight patients). Patients received a median of 4.5 courses (range, 2 to 12) of therapy. The median duration of survival was 228+ days (range, 81 to 540; six patients remain alive). Grade 3 or 4 toxicities occurred in three patients: diarrhea in two and mucositis in one. No toxicity-related hospitalization was reported. In summary, this combination showed promising activity and an acceptable toxicity profile in the treatment of Japanese patients with metastatic colorectal cancer.