Plasma concentrations of insulin, C-peptide, and proinsulin were measured in different vascular beds in order to determine renal, hepatic, and systemic kinetics of the endogenous peptides in the fasting condition. Nineteen nondiabetic subjects were studied, two were normal, nine had minor vascular disorders, four had cirrhosis without organic kidney disease, and four had organic kidney disease with moderately decreased glomerular filtration rate. In subjects without organic kidney disease the arteriorenal venous extraction ratios of insulin, C-peptide, and proinsulin were mean 0.27, 0.20, and 0.21, respectively (n = 14). These values were significantly reduced in kidneys with organic disease. Renal plasma clearance values of insulin, C-peptide, and proinsulin were mean 113, 87, and 90 mL/min, respectively (n = 6). Urinary clearances were substantially lower (0.8, 13, 3.5 mL/min, respectively), indicating that a significant degradation of these peptides also takes place in the normal kidney. In subjects without liver disease the estimated hepatic extraction ratio of insulin was mean 0.48, under the assumption that no C-peptide is removed by the liver. Endogenously released insulin was removed from plasma in kidney, liver, and elsewhere in the approximate proportion 10%:65%:25%, whereas, C-peptide was removed by one half in kidney and the other half elsewhere. The overall metabolic clearance rates of insulin and C-peptide were estimated to be 15 and 4.5 mL/min/kg, respectively. The results indicate that the kidney contributes substantially to removal of insulin, C-peptide, an proinsulin, mainly by degradation, less by urinary excretion.