Evidence suggests that metabolic abnormalities are responsible for the widespread microvascular complications of insulin-dependent diabetes mellitus (IDDM). Interest in endocrine pancreas replacement therapy, including pancreas transplantation, is based on the hope that such treatment will reverse the complications of IDDM by providing more precise metabolic control than conventional therapy. To determine if whole pancreas transplantation is capable of reversing well-established metabolic abnormalities of diabetes mellitus (DM) and maintaining strict metabolic control for life, we performed monthly metabolic studies for 2 years in 141 nondiabetic control rats, 273 diabetic control rats with alloxan-induced DM, and 267 diabetic rats that received syngeneic whole pancreaticoduodenal transplants 6, 9, 12, 15, 18, and 21 months after induction of DM with alloxan. Whole-pancreas transplantation in rats with long-standing DM permanently reversed the metabolic disorders. Elevated plasma glucose concentrations were permanently reduced to normal, depressed plasma insulin levels were permanently increased to normal, elevations of BUN and serum creatinine were permanently normalized, and there was a striking gain in body weight. Hyperglycemia during glucose tolerance tests was of lesser magnitude and shorter duration than normal, as a result of greater-than-normal plasma insulin levels. The only abnormality the persisted was hyperglycemia and is of unknown significance. These results indicate that whole-pancreas transplantation produces the most complete and sustained correction of the metabolic abnormalities of experimental DM of any available therapeutic modality.