IORT may be a potentially useful adjunctive treatment combined with surgery and/or external beam irradiation in treating locally advanced lung and esophageal tumors. To begin investigation of this modality, the tolerance of intact mediastinal structures to IORT was studied using adult American Foxhounds (wt. 25-30 kg). Groups of six animals received IORT to doses of 20, 30, or 40 Gy to two separate intrathoracic ports, using 9 MeV electrons to treat a portion of the collapsed right upper lobe, and 12 MeV electrons to treat the mediastinal structures. A group of three dogs received thoracotomy with sham irradiation. Two dogs from each treatment dose group, as well as one sham-irradiated control, were sacrificed electively at 1, 3, and 12 months following IORT. There were no acute nor late IORT related mortalities. Post-operative weight loss was minimal (average 4.5% of pre-operative weight) for all dogs. Serial esophagrams showed no inflammation or ulceration. No cardiac nor pulmonary changes were noted clinically. At autopsy, the irradiated lung showed evidence of acute pneumonitis at 1 month with progressive fibrosis at 3 months and 1 year. Esophageal reactions were minimal, with only two dogs (one 30 Gy and one 40 Gy) demonstrating histologically confirmed esophagitis at 1 month. Tracheal changes were minimal. Cardiac damage was evident in the right atrial tissues. In several dogs, this cardiac damage ranged from myocardial vascular changes to frank ischemic necrosis noted at 1 and 3 months, and dense fibrosis at 1 year. The phrenic nerves showed normal function, but had evidence of perineural fibrosis. The large vessels demonstrated only mild histologic evidence of irradiation. The results of this large animal study suggest that intact mediastinal structures will tolerate small volume IORT to doses of 20 Gy without significant clinical sequellae. Although the histologic changes in the right atrium and contralateral lung are worrisome, no cardiac nor pulmonary problems arose over the 1 year follow-up. Irradiation of the contralateral lung and other sensitive structures can be reduced by careful selection of electron beam energy and use of custom lead shielding.