The objective of the present study was to define the role of chemotherapy, in the form of the EP regimen, consisting of epirubicin (E) and cisplatin (P) in addition to irradiation in combination with 5-fluorouracil (5-FU) for treatment of pancreatic cancer. 53 eligible patients with histologically or cytologically proven locally advanced pancreatic cancer were treated with three cycles of E 60 mg/m2 (if this dose was well tolerated then the dose of E was increased by 10 mg/m2 in the next cycle; 80 mg/m2 was the maximum dose for the following cycles) and P 100 mg/m2 once every 3 weeks, followed after 4 weeks by a split course of irradiation of 40 Gy with 5-FU 500 mg/m2 on each of the first 3 days of each 20 Gy treatment segment. This was followed by another three cycles of EP in patients who achieved stable disease (SD) or a better response after the first three cycles. The treatment given with standard anti-emetics was moderately tolerated. The chemotherapy related toxicity consisted mainly of myelosuppression and the chemoradiotherapy related toxicity of gastrointestinal side-effects. However, due to the long duration of treatment which made the whole treatment difficult to endure, only 18/53 (34%) actually completed the full treatment regimen. Responses were evaluated after the first three cycles and 4 weeks after the completion of the treatment by serial CT-scans using standard criteria. The results in 53 evaluable patients after the first three cycles of EP were as follows: 1 patient achieved a clinical complete response (CR), 7 a partial response (PR) (CR + PR: 15%; 95% confidence interval (CI): 11-33%), 36 patients (68%) had stable disease (SD) and 6 patients progressive disease (PD). There was 1 early PD, 1 toxic death and 1 patient could not be evaluated. The response at the end of the treatment was 3 CR, 11 PR (CR + PR: 14/53 (26%); 95% CI: 15-40%), 30 SD and 6 PD. The median time to progression was 8.9 months and the median duration of response 13.1 months. The median survival of all treated patients was 10.8 months (range 7 days to 41.5 months), of responders 15.1 months and, of the patients with SD 10.3 months. These results are comparable to other combined modality regimens reported in the literature for locally advanced disease. The addition of the systemic treatment with E and P offers no additional advantage to combined modality treatment alone.