Exaggerated acute and late effects were observed in three of four women with pre-existing collagen vascular disease (CVD) within 2 years after definitive megavoltage radiation therapy for breast carcinoma. Five women with breast carcinoma, who developed CVD 3 months to 10 years after radiation therapy, had no complications. An abnormally severe reaction was observed during treatment of one patient with discoid lupus. The patient developed moist desquamation that persisted for a month, requiring early termination of treatment. One year after treatment, the patient developed paresthesias in the ipsilateral arm. A planned reduction of the prescribed dose in a second patient with progressive systemic sclerosis did not prevent intense erythema at the end of treatment, followed 14 months later by chest wall necrosis, which eventually required multiple surgeries including chest wall resections. The third patient, who had systemic lupus erythematosis, developed necrosis 2 years after treatment, which progressed over 12 years to osteoradionecrosis of the clavicle, sternum and rib cage. Multiple surgeries to repair the defect were complicated by flap necrosis and pleurocutaneous fistulas. The fourth patient died 6 months after radiotherapy without apparent sequelae. None of the patients had evidence of recurrent carcinoma. A history of collagen vascular disease appears to be a contraindication to breast conservation or for elective irradiation for breast cancer.