Bilateral adrenalectomy (BA) is a curative treatment for hypercortisolism in patients with corticotropin (ACTH)-dependent Cushing syndrome. Indications include refractory Cushing'sdisease (CD) following failed pituitary surgery, and occult or unresectable ectopic ACTH-producing neoplasms (EA). This was a single-center, retrospective review (1995-2017) of patients undergoing BA for CD or EA. Demographics, laboratory findings, and intraoperative and postoperative variables were analyzed. Of 137 patients, 83 (61%) had CD and 54 (39%) had EA; 87% of CD patients were female versus 46% of EA patients (p < 0.0001). Mean age at diagnosis was 40 ± 15years for CD and 49 ± 18years for EA (p = 0.004). Preoperative serum cortisol concentrations were higher in the EA cohort (63 ± 40μg/dL) versus the CD cohort (33 ± 19μg/dL) [p < 0.001], with no significant differences in serum ACTH. Time from diagnosis until adrenalectomy was 54 ± 69months for CD versus 4 ± 13 for EA (p = 0.002). Most patients underwent minimally invasive surgery (MIS; 86% CD vs. 75% EA; p = 0.19). There was no difference between the rates of conversion to an open approach, intraoperative blood loss, or operative time between groups, and no difference between complications in CD versus EA (p = 1.0). Five-year survival was significantly shorter among the EA cohort (30% for EA vs. 80% for CD; p < 0.001). Patients with EA presented with higher serum cortisol levels compared with patients with CD. EA patients were more likely to require intraoperative transfusion and postoperative intensive care. BA in patients with CD and EA can be performed safely in an MIS fashion, with similar morbidity; however, survival at 5years was significantly less in the EA cohort.