PURPOSE: Several surgical strategies have been proposed to treat MRI-negative Cushing's Disease. These include tumor removal, if identified, and if a tumor is not identified, resection of varying degrees of the pituitary gland, often guided by inferior petrosal sinus sampling (IPSS). The relative risks and benefits of each strategy have never been compared. METHODS: This systematic review of the literature included only studies on the results of surgery for MRI-negative patients with Cushing's Disease in which the surgical strategy was clearly described and associated remission and/or hypopituitarism rates detailed for each strategy. RESULTS: We identified 12 studies that met inclusion criteria for remission rates and 5 studies for hypopituitarism rates. We divided cases into 6 resection strategies. Remission and hypopituitarism rates for each strategy were: (1) tumor identified, resect tumor only (68%, 0%); (2) resect tumor and surrounding capsule (85%, 0%); and if the tumor was not identified (3) resect inferior 1/3 of gland (78%, no data); (4) resect 30-50% of gland based on IPSS (68%, 13%); (5) resect > 50% but < 100% of gland (65%, 9%); (6) resect entire gland (66%, 67%). Strategy 3 only contained 9 patients. CONCLUSION: Remission rates for MRI-negative Cushing's Disease support surgery as a reasonable approach. Results are best if a tumor is found. If a tumor is not identified, one can either remove one-third of the gland guided by IPSS lateralization, or remove both lateral portions along with the inferior portion leaving sufficient central gland to preserve function. Our recommendations are limited by the lack of rigorous and objective data.