OBJECTIVE 5-fluoracil (5-FU) remains the standard treatment in advanced colorectal cancer patients. An increasing number of recurring patients, however, have already received this drug as adjuvant after surgery. An attempt to increase 5-FU cytotoxicity through biochemical modulation is justified in this setting. In our study, a combination regimen of methotrexate followed by 5-FU, with leucovorin rescue, was employed. METHODS Patients were required to have symptomatic, measurable, inoperable lesions from colorectal cancer, recurring after adequate radical surgery of the primary tumor and adjuvant 5-FU + leucovorin concluded at least 3 months before recurrence. Patients received methotrexate. 250 mg/m2 as a 2-hour i.v. infusion, followed by two doses of 5-FU, 500 mg/m2 as i.v. bolus 1 hour and 21 hours after the end of methotrexate infusion. Leucovorin rescue, 15 mg orally every six hours for 7 times, was started 1 hour after the second 5-FU dose. The cycle was repeated every 2 weeks. RESULTS Twenty-two patients entered the trial, and 21 were evaluable. An objective response was observed in one patient (4.8%), 7 patients (33.3%) obtained tumor regression < 50% or disease stabilization. Thirteen patients (61.9%) progressed. Median survival in the whole group was 11 months. Subjective responses were observed in 7 patients (33.3%). Toxicity was mild. CONCLUSIONS Biochemical modulation with methotrexate does not seem a satisfactory means of increasing 5-FU activity, when the patient has been previously exposed to 5-FU plus leucovorin. On the other hand, any possible advantages in terms of quality and prolongation of life with this schedule were obtained at the cost of very acceptable toxicity.