Favorable results have been reported for the treatment of advanced colorectal cancer with the combination of 5-fluorouracil (5-FU) and leucovorin (LV). In these investigations the highest response rates were obtained in non-pretreated patients. In the present study, 22 patients with primary or acquired resistance to single-agent 5-FU and documented progressive disease on 5-FU were given a bolus injection of LV at a dose of 200 mg/m2, 1 h prior to a 2 h infusion of 5-FU at a dose of 370-770 mg/m2 on 5 consecutive days, and this was repeated every 3 weeks. Whenever possible the dose of 5-FU was escalated to find the maximum tolerable dose. No objective response was observed. Five patients had short-lasting stable disease. Despite 5-FU dose escalation, toxicity was acceptable. One patient developed 5-FU-related angina pectoris with EKG changes. It is concluded that in the schedule used, combined LV/5-FU treatment is ineffective for patients with 5-FU-resistant advanced colorectal cancer.