Background: Human melanoma cells express high-affinity glucocorticoid receptors, and adrenalectomy has been shown to have antimelanoma effects in animal models. Long-term regression of distant metastatic melanoma was observed in one patient after bilateral adrenalectomy, prompting a review of adrenalectomy for melanoma metastases performed at this center. Methods: A retrospective study in which all patients treated at the Sydney Melanoma Unit and recorded as having adrenal gland metastases between January 1987 and January 2004 were identified and their survival analyzed. Results: One hundred eighty-six patients with adrenal gland metastases were identified. Adrenalectomy was performed in 23 patients; the other 163 patients were treated nonsurgically. The adrenal glands were the sole site of disease in five patients. All symptomatic patients were free of pain after recovery from the surgical procedure. Thirteen patients were rendered clinically and radiologically disease-free by their surgery. There was no postoperative mortality within 30 days. Median overall survival after adrenalectomy was 16 months (2-year survival, 39%), compared with 5 months for patients with documented adrenal metastases treated nonsurgically (P < .00001). In one patient, nonresected visceral metastases elsewhere regressed completely after bilateral adrenalectomy; he remained well and free of disease 80 months after adrenalectomy. Regression of distant visceral metasatatic disease also occurred in a second patient after unilateral adrenalectomy. Conclusions: Adrenalectomy for melanoma metastatic to the adrenal gland provides good palliation of symptoms and is associated with prolonged survival in a selected cohort of patients. We report for the first time sustained complete regression of distant metastatic melanoma after bilateral adrenalectomy, suggesting a possible role for adrenal hormones in modifying melanoma progression in certain patients.