Asymmetric NG,NG-dimethylarginine (ADMA) and symmetric NG,NG-dimethylarginine (SDMA) are basic endogenous amino acids with a guanidino group. Our renal distribution study of dimethylarginines clearly indicates that, in mouse and rat, ADMA and SDMA levels are most abundant as protein-incorporated compounds (95%). ADMA represents almost 90% of this protein-incorporated dimethylarginine amount. The four zones studied (cortex, outer and inner stripe of outer medulla, inner medulla) contain more or less the same amount of protein-incorporated dimethylarginine; the concentrations of both free dimethylarginines vary more in the different zones. Plasma and urinary excretion levels in Man, rat and mouse were determined, their changes in renal insufficiency were examined and compared between species. Highly significant negative correlations between both plasma dimethylarginine levels and creatinine clearances were found in Man and rat. The correlation between urinary ADMA excretion levels and creatinine clearances was highly significant and positive in Man and mouse; however, in rat the correlation was negative. In patients with severe renal insufficiency, ADMA clearance was only 9.5% of controls, and that of SDMA only 7.8%. Clearance of ADMA and SDMA in nephrectomized mice was 60.5% and 53.8% of controls, respectively, whereas in nephrectomized rat, ADMA clearance actually increased 5.4 times and that of SDMA did not change significantly. Man, rat and mouse show similarities as well as differences in metabolism.