The incidence of cardiovascular disease is increased in diabetic nephropathy. Increased oxidative stress in diabetes is believed to play an important role in the pathogenesis of atherosclerosis in diabetes. Since antioxidant vitamins, such as ascorbic acid, often are reduced in diabetes, we hypothesized that the renal clearance of ascorbic acid is increased in patients with diabetic nephropathy. Thirty-seven subjects with diabetic nephropathy were studies: 18 had microalbuminuria (30-300 mg/day albuminuria); the remainder had clinical nephropathy (> 300 mg/day albuminuria). Indices of glycemic control (glucose, hemoglobin A1C) and renal function (albuminuria and creatinine clearance) were measured in addition to serum and urinary ascorbic acid levels. Results showed that subjects with clinical nephropathy had lower mean plasma ascorbic acid (p=0.0009) and higher renal clearance of ascorbic acid (p=0.005) than those with microalbuminuria. Bivariate analysis revealed an inverse correlation between creatinine clearance and AA clearance (r=-0.42, p=0.009). There was a significant linear association between the quantity of albuminuria and ascorbic acid clearance (r=0.49, p=0.002). Thus, patients with diabetic nephropathy have reduced ascorbic acid levels due to increased ascorbic acid clearance. The decrease in antioxidant defense that arises from the low levels of vitamin C may contribute to the increased cardiovascular morbidity and mortality observed in this population.