We determined the therapeutic effect of fluorouracil (5-FU) in combination with folinic acid (FA) in patients with measurable recurrent or metastatic carcinoma of the colon or rectum by comparing it to standard 5-FU therapy in a prospective randomized controlled trial. Patients were randomized to receive either FA, 200 mg/m2/d for five consecutive days, or nothing. All patients received 5-FU, 370 mg/m2/d for five days on the first course, with subsequent dose modifications to maintain equal toxicity in the two arms. One hundred thirty patients were entered on trial and only five were excluded from the analysis because they did not meet the eligibility criteria or they refused therapy after randomization. The two treatment arms were balanced for 11 clinical characteristics. Patients were evaluated for response at the end of every two treatment courses and toxicity after every course of therapy. Median follow-up was 1.45 years. Dose-limiting toxicity was mucositis and diarrhea on this treatment schedule, although neutropenia was apparent. The response rate was 33% (21 of 63 patients) in the 5-FU and FA arm and was 7% (four of 61 patients) in the 5-FU arm (P less than .0005). Time to disease progression was significantly different in the combination arm as compared with the single-agent arm (P = .023). Overall survival was significantly longer for patients treated with 5-FU and FA as compared with those receiving 5-FU alone (P = .05). The median survival was 12.6 months for patients receiving the combination, and 9.6 months for those receiving 5-FU alone. Our results indicate that the combination of 5-FU and FA is effective treatment for patients with metastatic or recurrent carcinoma of the rectum and colon who have not received prior chemotherapy.