We have reviewed our experience of adrenalectomy performed as part of the management of 56 patients with ACTH-dependent Cushing's syndrome between 1946 and 1993. Forty-three patients were operated on at our institution. Surgery-related mortality did not occur, but complications developed in 14 (33%); these were minor in 12. Eleven patients (29%) of the 38 for whom long-term follow-up data were available and who did not have a proven ectopic source of ACTH subsequently developed Nelson's syndrome, diagnosed on the basis of clinical pigmentation and markedly elevated ACTH levels that were not normally suppressible with glucocorticoids. The effects of prophylactic pituitary radiotherapy were assessed in 38 patients who underwent adrenalectomy at our institution and 18 who underwent surgery elsewhere. Patients who had received prophylactic radiotherapy were less likely to develop Nelson's syndrome (5 of 20, 25%) compared to those who did not (18 of 36, 50%; P > 0.07), and there was a low incidence of radiotherapy-induced hypopituitarism. We conclude that total adrenalectomy has proved to be a safe and effective operation and still may be indicated in selected patients with ACTH-dependent Cushing's syndrome; because prophylactic pituitary radiotherapy reduces the incidence of subsequent Nelson's syndrome by 50%, it should always be considered in the management of these patients.