The streptozocin (STZ)-diabetic nerve manifests increased morphological susceptibility to a superimposed acute ischemic injury, and reperfusion injury exaggerates ischemic nerve pathology. To determine whether STZ-diabetic nerves are susceptible to reperfusion, we evaluated the pathological consequences after 2.5 hours of ischemia followed by 3 and 24 hours of reperfusion in a 20-week STZ-diabetic rat sciatic nerve. After 3 hours of reperfusion, endoneurial edema developed in diabetic nerves, whereas non-diabetic controls showed mild or no edema. Morphometric analysis of endoneurial edema, quantified by the total transverse fascicular area and the point-count score of endoneurial structureless space, confirmed significantly more reperfusion-induced edema at thigh and knee levels in diabetic nerves than in controls. Reperfusion caused a significant increase in the number of endoneurial mast cells at the thigh level in diabetic nerves. After 24 hours of reperfusion, there were striking morphological anomalies of myelinated nerve fibers in diabetic nerves, without any observable changes in control nerves. In conclusion, we have demonstrated that STZ-diabetes exacerbates the morphological change to reperfusion. Diabetes therefore renders the microvasculature more vulnerable to the deleterious effects of ischemia/reperfusion.