PURPOSE: To compare the multimodality treatment results of surgical resection plus preoperative radiotherapy with concomitant protracted infusion chemotherapy (preop-chemoXRT), with or without an electron beam intraoperative radiotherapy (EB-IORT) boost, in 37 patients having advanced primary rectal cancer, with the results of a protocol using only preoperative radiotherapy (preop-XRT) plus surgical resection in a historic control group of 36 patients. METHODS AND MATERIALS: Thirty-eight patients with tethered T3 or T4 primary rectal cancer were treated with 45 Gy delivered in 25 fractions over 5 weeks plus infusional chemotherapy. Thirty-seven patients underwent surgical resection: 13 (35%) had restorative operations, and the remainder had either abdomino-perineal resection (APR) or pelvic exenteration (PE). Electron beam intraoperative radiotherapy (EB-IORT) was used in doses of 10-20 Gy for 11 patients with adherent pelvic tumor. In the 36 historic control patients, the preop-XRT dose was 45 Gy, and 93% of them had APR or PE. RESULTS: The local recurrence rate was 3% for the preop-chemoXRT group and 33% for the historic control group. The 3-year survival rate for patients treated with preop-chemoXRT plus resection was 82% compared with 62% for the historic control group. Distant metastases occurred more frequently in patients treated with an EB-IORT boost than in patients who were not (64% vs. 19%, p < 0.05), and the overall 3-year survival rate was lower for the former (67% vs. 96%, p < 0.05). Acute and late toxicities were acceptable. CONCLUSIONS: Preop-chemoXRT for advanced primary rectal cancer results in better control of pelvic disease and better overall survival rates than does preop-XRT alone. With preop-chemoXRT, acute chemoradiation toxicity is increased whereas late morbidity is unchanged compared with preop-XRT alone. Local control in patients with areas of residual or clinically adherent disease is improved by the use of EB-IORT; however, patients treated with EB-IORT had poorer survival rates than those treated without EB-IORT.