Little information has been reported on the metabolic characteristics of the totally pancreatectomized patient or the efficacy of medical management after radical pancreatic surgery. The prospective evaluation of 49 such patients, with 31% followed for 48 or more months, forms the basis of this report. The major immediate postoperative challenge is control of diarrhea and weight stabilization. Chronically patients have an increased daily caloric requirement (mean +/- SE, 56 +/- 1 kcal/kg), not wholly explained by moderate steatorrhea (fecal fat excretion, 16% +/- 2% of unrestricted fat intake). Despite persistent malabsorption, deficiencies in fat-soluble vitamin, magnesium, and trace element serum levels can be prevented in most patients. Pancreatogenic diabetes is characterized by (1) absence of the major glucoregulatory hormones insulin and glucagon, (2) instability, and (3) frequent hypoglycemia, with the latter parameters improving with rigorous home glucose monitoring. No patient has developed clinically overt diabetic micro- or macrovascular disease. Performance status in long-term survivors has been reasonable. However adverse chronic sequelae of the operation occur and include an unusual frequency of liver disease, characterized by accelerated fatty infiltration, and osteopenia, with an 18% reduction in radial bone mineral content noted in pancreatectomized patients studied more than 5 years after surgery.