Twenty-three patients with unresected, resected but residual, or locally recurrent biliary duct cancer were entered on a Radiation Therapy Oncology Group (RTOG) Phase I-II study. Of 16 patients who were properly entered and eligible for study, eight patients (50%) completed protocol treatment including intraoperative radiation therapy (IORT). Minor acute complications from therapy were common. There was no early grade 3 or 4 toxicity. Major long-term toxicity (grade 4) was noted in one patient who suffered a perforated viscous related to salvage radiation therapy for a scar recurrence and died of infection 1 month after retreatment. With a median follow up of 10.5 months, two of the eight patients who received IORT are alive. Of the six patients who died, one had persistent disease, one had the tumor recur in the surgical wound and subsequently died of complications related to retreatment with high dose radiation, and one died of intercurrent disease. In addition, two patients died with liver metastasis, and one died with intraabdominal disease outside of the IORT volume. Bulk of disease may be an important determinant of outcome.