Twenty patients with inoperable locally advanced Stage II and III pancreatic cancer were treated with combined modality therapy. Radiotherapy consisted of split courses of 2000 cGy each and, as needed, an additional 1400 cGy, separated by 2-week intervals. Simultaneous multidrug regimen chemotherapy consisted of 5-fluorouracil, continuous infusion, 1 g/m2 days 1-5; streptozotocin, 300-500 mg/m2 days 1, 2, 3; and cisplatin, 100 mg/m2 day 3 of every 4-week radiotherapy course (RT-FSP). Primary tumors decreased more than 50% in volume in 11 of 20 patients. Computed tomography scans demonstrated apparent complete disappearance of the primary tumor in 7 patients. Only 3 patients had tumor regrowth within the radiotherapy field, all after the end of radiotherapy. Local control improved as measured by increased frequency of tumor shrinkage and decreased frequency of primary tumor growth, recognizing the limitations of a pilot study and comparisons to best historical results achieved with standard short 5-fluorouracil schedules and radiotherapy. Successful local control largely eliminates the most common cause of refractory pain and may decrease the need for some forms of early palliative surgical intervention. Tumor shrinkage sometimes downstages tumors, creating frequent investigational opportunities for either elective extirpative surgery or intraoperative radiotherapy. This pilot experience also supports testing of expanded eligibility staging criteria for combined modality treatment and testing of new drugs as part of 5-fluorouracil-radiotherapy-based regimens.