BACKGROUND: Several cases of long term radiation sequelae have been reported in patients with lupus erythematosus and systemic sclerosis after breast or chest wall irradiation. To the authors' knowledge, no experience with such complications in patients with mixed connective tissue disease (MCTD) has been reported previously. METHODS: A case of a woman with occult breast carcinoma metastatic to the axilla and preexisting MCTD is presented. To the authors' knowledge, this is the first case report of the adverse effects of breast irradiation in a patient with MCTD. The pathophysiology of such radiation injury to specific anatomic structures and technical dosimetric considerations of the radiation therapy and radiation dose are analyzed. The relevant literature on other collagen vascular diseases with features related to MCTD is reviewed. RESULTS: A moderate dose of radiation to the breast and regional lymphatics resulted in marked early and late toxicity to skin and subcutaneous tissues. The tissue injury was similar to that observed in patients with lupus erythematosus and systemic sclerosis. The early skin reaction (moist desquamation) was related to the daily radiation dose delivered at the depth of the epidermis, and the late reaction (subcutaneous fibrosis) was related to the dose at the depth of the dermal capillaries and dermal connective tissue. CONCLUSIONS: Patients with MCTD may develop exaggerated radiation reactions similar to those in patients with lupus erythematosus and systemic sclerosis. Although the incidence of such radiation reactions in patients with MCTD is difficult to assess, the risks and benefits of radiation therapy should be carefully weighed in these patients, particularly if an alternative therapy is available. If there is no alternative, judicious attention to radiotherapy technique may reduce or prevent skin toxicity.