A prospective neoadjuvant trial utilizing chemotherapy (CTX) and radiotherapy (XRT) prior to pancreatectomy was established to determine the feasibility of resection after aggressive pretreatment and its effect on survival. Fifteen patients with pancreatic cancer (14 head, 1 body) and 1 patient with duodenal cancer, (with paraaortic adenopathy), were subjected to combination treatment with infusional 5-FU, bolus injection of mitomycin-C, and XRT (4 patients were treated off the protocol). Patients were restaged 3 wk after XRT, and those deemed resectable underwent a pancreatic resection. Three patients did not undergo exploration after the neoadjuvant therapy, although two of these were deemed resectable by CT scan. The remaining 13 patients underwent exploration and 10 underwent resection. Three did not undergo resection because of extrapancreatic disease, although their primary tumors were resectable. One patient had no residual tumor in the specimen. The others had residual tumor with evidence of necrosis and hyalinization, but all margins were free of tumor. There were two perioperative deaths from sepsis. Of the remaining patients who underwent resection, one died of a myocardial infarction at 9 mo. One patient died with recurrent disease at 19 mo. The remaining patients are alive 40, 32, 11, 11, 10, and 4 mo since diagnosis and are currently free of disease. Aggressive neoadjuvant chemoradiotherapy can be performed safely, allows successful resection, and may yield long-term survival or curve.