Oxidative stress is implicated in the pathogenesis of diabetes mellitus. We investigated whether or not oxidized protein hydrolase (OPH), which preferentially degrades oxidized and glycated proteins, has a preventive or delaying role in diabetes mellitus. Using streptozotocin (STZ)-induced diabetic Wistar and Goto-Kakizaki (GK) rats as models of types 1 and 2 diabetes, respectively, we traced the changes in serum and urinary OPH activity with the pathological progress. Serum OPH activity increased nearly in parallel with increases in the blood glucose level in the two rat models, clarifying first in this study that serum OPH activity increases from a very early stage of diabetes. These findings suggest that increased serum OPH has at least a delaying action against the progression of diabetes through the removal of damaged proteins. Urinary OPH activity increased only in STZ-induced diabetic rats with microalbuminuria, but not in GK rats still without marked renal disorder, indicating the leakage of circulating OPH; the increase in urinary OPH activity may be a useful marker for diabetic nephropathy. OPH may provide a new therapeutic strategy against diabetes and its complications.