Localization and surgical treatment of occult insulinomas. Management of patients with biochemical evidence of insulinoma and negative preoperative imaging studies (occult) tumors is controversial, varying from primarily medical management to aggressive, blind nearly total pancreatectomy to extirpate the tumor. Since 1982, 12 consecutive patients with occult insulinoma underwent preoperative portal venous sampling (PVS) for insulin followed by surgical exploration with intraoperative ultrasound (IOUS). Eleven of twelve patients (92%) had insulinoma removed and were cured. Portal venous sampling correctly predicted the location of the insulinoma in 9 patients (75%) and that no tumor would be found in another patient. A fourfold insulin gradient in the pancreatic tail of one patient correctly predicted that a distal pancreatectomy would remove the insulinoma despite the fact that neither palpation nor IOUS identified any tumor. Intraoperative ultrasound was the single best method to identify occult tumors because it correctly identified 10 of 11 insulinomas that were found, including five pancreatic head tumors that were not palpable. Palpation identified five insulinomas. Of the 10 tumors that were identified during operation by palpation or ultrasound, IOUS identified significantly more (100% versus 50%, p = 0.03) and guided the successful enucleation of each. The results support the strategy of preoperative PVS and operation with IOUS to localize and remove insulinoma in patients with occult tumors. Most tumors (75%) will be correctly localized to a specific pancreatic region by preoperative PVS and identified by IOUS (83%), allowing simple enucleation and biochemical correction of hypoglycemia. Morbid blind pancreatic resections are no longer indicated and long-term medical management of hypoglycemia should be reserved for the occasional patient (8%) who fails preoperative PVS and operation guided by IOUS. 