Paraoxonase-1 (PON1) is an HDL cholesterol-associated antioxidant enzyme, and some of its polymorphisms are linked with systemic oxidative stress and cardiovascular events. In this study, we genotyped seven single nucleotide polymorphisms (SNPs) within the PON1 gene and determined their association with chronic kidney disease in 2,968 individuals from the general Japanese population. We found that a missense SNP (rs662) with a G-to-A substitution leading to an amino acid substitution (G[Arg]/A[Gln]), was significantly associated with albuminuria and estimated glomerular filtration rate (eGFR), especially in women. The A/A genotype in women had the highest prevalence of albuminuria and the lowest values of adjusted eGFR. In contrast, such relationships were not detected in men. Multivariate regression analysis found that the A/A genotype was an independent and significant factor for albuminuria and renal insufficiency (eGFR less than 60 ml/min/1.73 m(2)). The serum PON1 activity was lowest in subjects with the A/A genotype. In biopsy specimens, immunohistochemical analysis found increased PON1 expression on the endothelial surface of sclerotic renal arterioles and glomerular capillaries in patients with hypertension or diabetes. Our study shows that this PON1 G-to-A substitution may be a key player in a common pathway to chronic kidney and cardiovascular diseases in women.