Large, adrenocorticotrophic hormone-secreting pituitary tumors (Nelson's syndrome) developed in four of 12 patients treated with a bilateral adrenalectomy for Cushing's disease. Two of the patients with Nelson's syndrome suffered spontaneous pituitary tumor infarctions. One patient improved under close observation and subsequent radiation therapy, although she ultimately died from her locally invasive tumor. The condition of the other patient-which had stabilized-appeared to be worsened by surgical intervention. The high incidence of these tumors after bilateral adrenalectomy, their large and agressive nature, and their apparent propensity to undergo spontaneous infarction supports the position that initial therapy for Cushing's disease should be directed to the pituitary gland.