Intraoperative radiation therapy (IORT) is capable of delivering high doses of radiation to mediastinal structures while sparing lung parenchyma, heart, and other locoregional tissues. A canine model of pulmonary resection and IORT was investigated by performing a pneumonectomy in 15 adult foxhounds followed by 0 cGy, 2,000 cGy, 3,000 cGy, 4,000 cGy. No clinical complications developed in 4 animals in the 2,000-cGy group. However, 2 of the 8 animals given a high dose died of esophageal hemorrhage or carinal necrosis. Esophagitis occurred in 10 of 12 animals, and none of the animals experienced bronchial stump dehiscence. In a limited Phase I protocol, 4 patients with non-small cell lung cancer were treated with resection and 2,500 cGy of IORT to two separate ports encompassing the superior and inferior mediastinum. Two patients experienced life-threatening bronchopleural fistulas, and 2 patients died as a consequence of esophageal problems. One patients had recurrence with brain metastases, and the 1 long-term survivor is free from disease. As opposed to the animal model of thoracic IORT, the clinical study demonstrated major toxicity with respiratory and esophageal morbidity. The therapeutic usefulness of thoracic IORT in the management of lung cancer must be questioned in view of this small but consistent series of patients. Further carefully designed clinical studies using lower doses of IORT are needed.