PURPOSE: In an effort to reduce relapse in the liver and improve survival in patients with potentially resectable adenocarcinoma of the pancreatic head, we combined whole-liver irradiation with our standard preoperative chemoradiation regimen. METHODS AND MATERIALS: Eleven patients with biopsy-proven, potentially resectable adenocarcinoma of the pancreatic head were treated with 50.4 Gy of external beam irradiation to the pancreas (1.8 Gy/day, 5 days/week) and concurrent continuous infusion 5-fluorouracil (300 mg/m2 per day). The liver was treated with 23.4 Gy on Days 8 through 21 (13 fractions; 1.8 Gy/fraction). Patients, who upon restaging with radiography and computed tomography were considered to have resectable tumors, were subsequently taken to surgery. If, at surgery, tumors were resectable, pancreaticoduodenectomy was performed, and 10 Gy of intraoperative electron-beam radiation therapy was delivered to the bed of the resected pancreas. RESULTS: All 11 patients completed chemoradiation. Two treatment-related deaths occurred following chemoradiation, prompting premature termination of the study. Of seven patients taken to surgery, four underwent resection. Seven patients have died of disease, five with liver metastases. CONCLUSIONS: Prophylactic hepatic chemoradiation, as given in this study, was associated with two treatment-related deaths and a higher than expected incidence of subsequent liver metastases. Our data do not support the use of this treatment program in patients with adenocarcinoma of the pancreas.