OBJECTIVE - Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy. RESEARCH DESIGN AND METHODS - ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 μmol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]). RESULTS - In patients with diabetic nephropathy, mean ± SD plasma ADMA concentration was elevated 0.46 ± 0.08 vs. 0.40 ± 0.08 μmol/l in normoalbuminuric patients (P < 0.001). An increase in plasma ADMA of 0.1 μmol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P < 0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (≤76 ml · mm -1 · 1.73 m-2) (P < 0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P > 0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 ± 0.08 μmol/l compared with 0.46 ± 0.08 μmol/l in patients without major cardiovascular events (P = 0.05). CONCLUSIONS - Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.