To answer the crucial question regarding reversibility of diabetic somatic neuropathy by whole-pancreas transplantation, metabolic studies and electron microscopic morphometry of the sciatic and testicular nerves were performed monthly for 2 years in three groups of highly inbred rats: (1) NC, 47 nondiabetic controls; (2) DC, 90 untreated alloxan-induced diabetic controls; and (3) DT, 230 diabetic rats given syngeneic pancreaticoduodenal transplants 6, 9, 12, 15, 18, and 21 months after induction of diabetes mellitus (DM). Six diabetic nerve lesions were quantitated by a "blind" protocol: (1) loss of myelinated axons, (2) intraaxonal glycogen deposits, (3) axons with glycogen deposits, (4) demyelinated axons, (5) degenerating axons, and (6) loss of intact axoglial junctions in paranodal terminal myelin loops. In the DT group, testicular nerve specimens were obtained just before transplantation and at death so that each animal served as its own control. As we have observed previously in untreated diabetic controls, all six nerve lesions progressed relentlessly for 2 years, in contrast to nondiabetic controls (p less than 0.01). Whole-pancreas transplants produced complete metabolic control of DM for life and reversed all six lesions in both sciatic and testicular nerves, even when done late in the course of DM. There was complete reversal of the nerve lesions when pancreatic transplantation was done within 15 months of the onset of DM. These results provide the first demonstration of reversal of diabetic somatic neuropathy by any form of DM therapy and extend our previous work in which whole-pancreas transplants were found to prevent both diabetic neuropathy and nephropathy and reverse mesangial enlargement in the kidney.