Objective. - To determine whether optimized glycemic control in type I diabetic recipients of renal allografts will prevent or delay diabetic renal lesions in the allograft. Design. - Prospective, controlled, and randomized trial of glycemic control in an inception cohort of type I diabetic renal allograft recipients. The experimental group underwent maximized glycemic control, and the standard group was treated in the same way as other patients in the transplant clinic. Patients underwent baseline (before transplant) and 5-year posttransplant allograft biopsies. Setting. - University of Minnesota Hospital and Clinic and the Clinical Research Center and Hennepin County Medical Center, Minneapolis. Patients. - Type I diabetics with terminal diabetic renal failure undergoing renal transplantation. Forty-eight patients randomized to maximized or standard control completed the trial. Intervention. - Subcutaneous insulin given several times a day or continuously (maximized group) and once or twice each day (standard group) was used throughout the trial. A significant difference for hemoglobin A1 level was maintained (mean±SD; standard, 0.117±0.013; maximized, 0.096±0.016; P<.001). Main Outcome. - The primary end point of this trial was the difference between the groups in renal glomerular mesangial expansion as determined by electron microscopy. Results. - There was a more than twofold increase in the volume fraction of mesangial matrix per glomerulus in the standard group (mean±SD, 0.043±0.034) compared with the maximized group (0.019±0.038; P=.024). The threefold increase in arteriolar hyalinosis, the greater widening of the glomerular basement membrane, and increase of volume fraction of the total mesangium in the patients who received standard treatment all approached significance (P=.10 or less). The incidence of severe hypoglycemic episodes was greater in the maximized group (1.7 per patient per year) than in the standard treatment group (<0.1 per patient per year; P<.001). Conclusions. - This trial indicates a causal relationship between hyperglycemia and an important lesion of diabetic nephropathy, mesangial matrix expansion, in renal allografts transplanted into diabetic recipients. In addition, the results with other lesions central to the development of diabetic nephropathy support the major conclusion.