Patients (26) with metastatic colorectal adenocarcinoma were entered into a Phase I-II study of 5-fluorouracil (5-FUra)-high-dose leucovorin (CF). The starting dose of 5-FUra was 300 mg/m2 with escalation to 750 mg/sq2 per wk in 6 doses given by rapid i.v. injection midway during a 2-h infusion of CF, 500 mg/m2. Partial responses were seen in 9 of 23 patients (6 of 12 who had previous 5-FUra). Complete normalization of liver enzymes was seen in 2 of these patients. Side effects were seen sporadically with 5-FUra doses up to 600 mg/m2. At a 600-mg/m2 5-FUra dose, 8 of 18 patients had diarrhea and 2 of 18 had white blood cell counts < 3000/.mu.l. At a 750-mg/m2 dose of 5-FUra, 6 of 11 patients had severe diarrhea and 6 of 11 had white blood cell counts < 3000/.mu.l. Other toxicities were mild conjunctivitis and lacrimation, thinning of the nails and alopecia. In bioavailability studies of CF p.o., no plasma CF could be detected. After CF i.v., mean plasma peak was 111.3 .+-. 40.3 (SD) .mu.M. 5-FUra-CF appears to be effective in patients clinically resistant to 5-FUra. This study is being extended to randomized trial of 5-FUra-CF vs. 5-FUra alone.