Treatment of locally advanced pancreatic cancer with high-dose radiotherapy has not been curative, and can be difficult to tolerate. We decided to compare retrospectively the outcomes of patients treated concurrently with 5-fluorouracil and either 30 Gy or more than 30 Gy of radiation. From December 1993 through May 2001, 107 patients with locally advanced adenocarcinoma of the pancreas had been treated with palliative chemoradiation. Eighty-six patients had received a prescribed dose of 30 Gy and 50.4 Gy had been prescribed in 18 patients. Two of these patients were unable to complete the full dose of radiotherapy due to toxicity, and 3 received intraoperative radiotherapy boost (20 Gy). Three additional patients received a prescribed dose of 33 Gy, 36 Gy, and 52.2 Gy, respectively. These patients were grouped together (n = 21, median 50.4 Gy). All patients had received concurrent protracted venous infusions of 5-fluorouracil (300 mg/m Monday through Friday). The median survival time was not affected significantly by a higher radiotherapy dose (8 months for the 30 Gy group versus 9 months for the group receiving higher doses; P = 0.64). The 6-month actuarial progression rates were 45% versus 50% (P = 0.90) for local disease progression, and 54% versus 50% (P = 0.94) for distant metastasis for the 30 Gy and the higher dose groups, respectively. Ten of the 86 patients (12%) who had received 30 Gy were hospitalized for treatment-related gastrointestinal toxicity (grade 3) versus 6 of the 21 (29%) patients given higher doses (P = 0.05). Compared with higher doses given over 5 to 6 weeks, chemoradiation (30 Gy in 10 fractions in 2 weeks with concurrent infusional 5-FU) results in a similar median survival, and local disease progression rates in patients with locally advanced pancreatic cancer apparently do not substantially improve local disease control or median survival time. Because higher doses of radiotherapy can lead to increased acute treatment-related morbidity, we recommend using 30 Gy in 10 fractions unless the patient is part of a prospective study evaluating novel biologic or cytotoxic radiosensitizers.