Twenty-two patients with metastatic colorectal cancer were treated with a regimen of 5-fluorouracil 600 mg/m2 (maximum, 1.0 g) i.v./week and folic acid 140 mg/m2 i.v. given 1 h prior to the 5-FU. This study was undertaken in an attempt to confirm the in vitro finding that inhibition of thymidylate synthetase by 5-fluorouracil is prolonged by the presence of folates. There were four partial responses (18%) with mean duration 4 months. Dose-limiting toxicity was enteritis, seen in 12 patients (58%), and causing hospitalization in seven patients. Enteritis was shown to be due to the folic acid in most patients. Two patients died from leukopenia, enteritis, and sepsis. Mean serum folate levels at the time of 5-FU injection were 36 microM. This regimen is no more effective than 5-FU alone and has significantly more serious toxicity. Further investigation of this regimen is not recommended.