To compare the efficacy of two biochemical modulations of 5-Fluorouracil in advanced colorectal cancer, 104 patients were randomized to receive high dose methotrexate followed by 5-Fluorouracil and leucovorin rescue on day 1 (Arm A) or folinic acid and 5-Fluorouracil on day 1 to 5 (Arm B). Both treatments were repeated every 3 weeks. In the 92 evaluable patients, objective responses were observed in 34% in Arm A and 31% in Arm B, with a median duration of 7.5 and 8.5 months, respectively. Median overall survival was similar in both groups (12 versus 13 months, respectively). A statistically significant difference was found only between responders and non responders of group B (p = 0.004). Toxicity was mild. In conclusion, no difference in therapeutic activity was seen between the two treatments and additional biochemical modulation must be evaluated.