We have performed a prospective randomized controlled study of 5-fluorouracil (5FU) + leucovorin versus 5FU alone in patients with metastatic colorectal cancer. The 5FU at a dose of 370 mg/m2/d x 5 days and the leucovorin at a dose of 200 mg/m2/d x 5 days were given every 28 days. The 5FU dose was escalated to equitoxicity in the single agent arm on subsequent studies. The response rate was 33% for the combination and only 7% for 5FU alone. The median survival for 5FU + leucovorin was 12.6 months and 9.6 months for 5FU alone. The dose-limiting toxicity was mucositis with diarrhea being the second most common problem. The combination of 5FU + leucovorin is an effective treatment in the management of patients with metastatic colorectal cancer and should be used as a foundation from which to build upon.