Background. The purpose of this study was to evaluate the use of intraoperative electron beam radiotherapy (IORT) as an adjuvant modality in the treatment of advanced head and neck and skull base cancer. Methods. Between 1991 and 1996, 34 patients with squamous cell carcinoma (SCCA) and 10 patients with non-SCCA were enrolled in this prospective nonrandomized clinical trial. Most patients had been previously treated with combinations of surgery, external beam radiotherapy, and chemotherapy. The most frequent sites treated were the skull base (56%) and the neck (44%). IORT was delivered in a dedicated operating room suite with energies of 6 to 15 MeV (6 MeV most commonly used) at doses of 12.5 to 22.5 Gy. Results. At 2 years overall and disease-free survival was 32% and 21%, respectively, for the SCCA patients and 50% and 40%, respectively, for the non-SCCA patients. Tumor control rates at 2 years in the IORT field were 46% for the SCCA patients and 52% for the non-SCCA patients. For squamous cell histology, survival in patients with microscopic residual tumor did not differ from those with no residual tumor, but they both had significantly longer disease-free survival than those patients with gross residual at the time of IORT (p = .03), with a trend toward longer overall survival (p = .09). The only complication directly attributable to IORT was a neuropathy in a patient who received an IORT dose of 22.5 Gy (cumulative dose 130.1 Gy). Conclusions. IORT at a dose of 12.5 Gy is safe and produces tumor control and survival for patients likely to have microscopic residual disease in sites difficult to resect such as the skull base. © 2003 Wiley Periodicals, Inc.