5-Fluorouracil (5-FU) modulation with either folinic acid (FA) or methotrexate (MTX) has improved 5-FU's potential cytoreductivity. We combined MTX and FA with 5-FU to further augment 5-FU's cytoreductivity. Patients (n = 34) with advanced colorectal carcinoma were first given intravenous MTX (escalated from 30 mg/m2 to 70 mg/m2). FA (100 mg/m2) was infused 17-24 hr later, followed by 5-FU (600 mg/m2). Oral rescue doses of FA were begun 24 hr after MTX. Patients were treated every 2 weeks. No previously treated patient (n = 6) responded. Eight of the remaining 28 (29%) (95% confidence interval, 15-47%) patients achieved a PR. Median survival was 9.3 months. Toxicity (primarily gastrointestinal) necessitated dosage modification in 10 patients (29%). These results, in addition to a literature review, reveal that the manipulation of 5-FU by two modulating agents does not improve the response rate seen with single-agent modulation.