The combination of 5-fluorouracil (5-FU) and folinic acid (FA) has demonstrated activity in most gastrointestinal tumors. The addition of epirubicin (EPI) may increase the efficacy of the combination for cancers of the upper gastrointestinal tract, such as advanced pancreatic cancer. We examined two groups of patients, explaining the potential benefits and limitations of therapy, and those patients who agreed to undergo chemotherapy formed Group A and the remaining formed Group B. Therefore, the study was a non-randomized prospective comparison between patients receiving chemotherapy and those offered the best supportive care. Group A consisted of 42 patients; 19 underwent Roux-en-Y operation, and 23 were inoperable. Group B consisted of 48 patients who refused chemotherapy; 18 underwent Roux-en-Y operation, and 30 were considered inoperable. Chemotherapy consisted of FA 200 mg/m2/day, 5-FU 600 mg/m2/day both for 5 days, and EPI 35 mg/m2/day before FA-5-FU administration on days 1 and 2, every 28 days. All patients were evaluable for response and toxicity. Objective tumor responses (partial responses) in Group A were seen in 8 patients (19%) (6 women and 2 men), and 6 (14%) had stable disease. The estimated median survival was 27.6 weeks (mean 27.5) for Group A and 22.5 weeks (mean 24) (p=0.01) for Group B. From the onset of therapy, median duration of response was 16.6 weeks and median time to progression 11.8 weeks in Group A. Toxicity consisted primarily of myelosuppression, nausea and vomiting, diarrhea, alopecia, and mucositis. In Group A 12/42 patients became free from pain for a median duration of 10 months, 14/42 had improved appetite, and 15/42 had improved performance status in comparison to Group B, where no patients had improved performance status or symptoms. We conclude that the combination of EPI+FA+5-FU has moderate activity and increased toxicity in the treatment of advanced pancreatic cancer.