A phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil (5-FU), leucovorin, and inteferon &agr;-2a in metastatic pancreatic carcinoma. Twenty-three patients were entered in this study. Four patients withdrew before receiving treatment and one patient was nonevaluable for response because of treatment-related toxicity. The most common significant toxicity was nausea and vomiting. Treatment-related hospitalization was significant. Of 18 evaluable patients, 4 maintained stable disease and 14 had disease progression. None had an objective clinical response. We conclude that this biochemically modulated 5-FU regimen is ineffective treatment for advanced pancreatic carcinoma, with significant toxicity even in highly selected patients with an ambulatory performance status.