It is possible that myeloperoxidase (MPO) contributes to the pathogenesis of diabetic nephropathy through the production of reactive oxygen species and HOCl/OCl⁻. In this study, we examined the relationship between renal damage and MPO G-463A gene polymorphism that is associated with its transcription activity in diabetic patients. We evaluated the association between MPO G-463A polymorphism and the prevalence of proteinuria and estimated GFR (eGFR) in 1448 Japanese type 2 diabetic subjects. The prevalence of macroalbuminuria was higher as the number of G alleles increased (GG (7.6%), GA (3.8%), AA (0.0%), p for trend=0.0269). The number of G alleles was significantly associated with macroalbuminuria (odds ratio 2.12, 95%CI 1.06-4.24, p=0.0344) even after adjustment for conventional risk factors. Inversely, eGFR was lower as the number of G alleles increased (GG (76.7±20.7 mL/min/1.73m²), GA (81.0±22.8 mL/min/1.73m²), AA (92.0±23.1 mL/min/1.73m²), p for trend=0.0025) and the number of G allele was an independent risk factor for a low eGFR (β=-0.072, p=0.003). We also examined the association between MPO expression and several stages of renal damage in a high-fat diet-induced diabetic mouse model. The proteinuria-induced increase in MPO expression was markedly enhanced in diabetic mice, and MPO expression was significantly correlated with the severity of kidney damage. In conclusion, it is likely that the G allele of the MPO G-476T polymorphism is a susceptibility allele for renal injury in type 2 diabetic patients.