Eighteen patients with unresectable localized adenocarcinoma of the pancreas were treated by a combination of chemotherapy plus hyperfractionated radiation therapy to the pancreas for 4080 cGy with an additional 960 cGy to the pancreatic tumor and a surrounding margin. One hundred and twenty cGy were given twice daily 4 to 6 hours apart. High-energy photon or electron beams were used with treatment planning based on computed tomographic (CT) scans. Patients were given chemotherapy in the form of 5-fluorouracil (5-FU) at 350 mg/m2 on the first 3 and last 3 days of radiation therapy. On day 53, chemotherapy was given that included 600 mg/m2 IV of 5-FU, 1 gm/m2 of streptozotocin, and 10 mg/m2 IV of mitomycin C. The 5-FU and streptozotocin were repeated on days 60, 81, and 88, and the stretozotocin and mitomycin (SMF) cycles were repeated every 8 weeks until progression. Radiation toxicity was generally tolerable with one of 18 evaluable patients having severe nausea and vomiting and two of 18 patients having severe diarrhea. One patient had total liver failure and died 3 months after initiation of therapy. Six patients had severe hematopoietic toxicity during chemotherapy. Overall, the severe toxicity rate was higher (67%) than in previous studies. Median survival was 35 weeks, the 1-year survival rate was 39%, and the patient who survived the longest died at 68 months. Although this schedule of hyperfractionated radiation and chemotherapy was disappointing, combined experimental radiation approaches plus chemotherapy for localized unresectable adenocarcinoma of the pancreas deserve additional research.