In a phase II study, 38 previously untreated patients with metastatic colorectal carcinoma were treated with continuous intravenous infusion of 5-fluorouracil (5-FU) 750 mg/m2 daily for 5 days, followed by weekly bolus 5-FU at 750 mg/m2 and subcutaneous interferon (IFN) at 9 million units three times per week. Of 35 evaluable patients, nine (26%) achieved a partial response (95% confidence limit, 11% to 41%), with a median response duration of 7.5 months (range, 4.4 to 17+ months). Seven patients (20%) had a minor response, and 10 (28%) had stable disease. The median length of survival was 13 months (range, 2 to 19+ months). The most common toxicities observed were stomatitis (52%) and diarrhea (43%). Neurotoxicity was seen in 34% of patients and consisted of gait disturbance, dizziness, confusion, memory loss, and dementia. Because of toxicity, 84% of patients required a reduction of the IFN dose by at least 50%, and 63% required reduction of 5-FU by at least 25%. We conclude that while the combination of 5-FU and IFN in patients with advanced colorectal carcinoma has some activity, the regimen is toxic and the observed response rate (26%) is not substantially superior to alternative 5-FU programs.