The purpose of this study is to assess the feasibility, clinical tolerance, local control, and survival rates using a combined-modality treatment program of intraoperative radiation, chemotherapy, and external beam radiation for the management of patients with pancreatic cancer. One hundred eighty patients with biopsy-proven adenocarcinoma of the pancreas have been treated by a single surgical practice between 1979 and 1992. Of these, 105 had locally advanced but unresectable primary tumors (stages 2 and 3). All patients were treated with a program of multimodality therapy, including surgery, chemotherapy, and radiation therapy. Three groups were identified. Group I (33 patients) received intraoperative radiation therapy (IORT) as part of their treatment. Group II (43 patients) received intraoperative radiation in the form of iodine-125 (I-125) implantation. Group III (29 patients) received no intraoperative radiation. All three groups were comparably similar with respect to age at presentation, amount of preoperative weight loss, preoperative symptoms, and tumor location. Overall perioperative mortality was 4.8 per cent (five patients), with no difference between groups noted. Perioperative complications occurred in 32 (30.4%) of the 105 patients. Complications occurred in only 18.1 per cent of patients in Group I (IORT), compared with 39.5 per cent of Group II (I-125) patients (P < 0.01). Group III patients (no intraoperative radiation) experienced complications in 31.0 per cent of cases (P = 0.09 vs Group I). Actuarial survival was 18 months for Group I (IORT) versus 15 months for Group II (I-125). One- and 2-year actuarial survival rates were 60 and 17 per cent for patients in Group I (IORT) and 56 and 19 per cent for Group II (I-125). Actuarial local control rates for patients receiving IORT (Group I) was 70 per cent at 2 years. Patients with pancreatic cancer historically have poor survival and local control rates despite aggressive chemotherapy and radiation. The addition of intraoperative radiation to the combined modality management of pancreatic cancer offers markedly improved survival rates and local control with minimal morbidity for patients with unresectable disease. Intraoperative radiation in the form of IORT can be delivered with a significantly fewer complications than I-125 seed implantation.