This study was performed to test the hypothesis that the kidneys play a primary role in the clearance of endogenous leptin from the circulation. Lean male Sprague-Dawley rats were anesthetized and subjected to various surgical manipulations of the kidneys. Sixty minutes after surgery arterial blood samples were taken at 1-h intervals for up to 8 h. Plasma leptin levels were determined by radioimmunoassay. Bilateral nephrectomy induced a rapid increase in plasma leptin concentrations above control values, indicating that the kidneys are important for the elimination of leptin from the circulation. Leptin was not metabolized across the renal circulation and was extracted intact by the kidney. Simultaneous measurement of renal plasma flow established renal leptin extraction at approximately 6.5 ng/min for both kidneys. Compared with the quantities extracted from the plasma, leptin was only present in the urine in small quantities, indicating extensive metabolic degradation in the renal tubules. High plasma leptin levels were not maintained after binephrectomy indicating that pathways other than the kidneys are also responsible for leptin clearance. Seven hours after bilateral ureteral ligation, a procedure which lowers glomerular filtration, plasma leptin levels were slightly elevated. The renal extraction of leptin did not change over a wide range of plasma leptin concentrations suggesting that renal leptin extraction is a high capacity, non-saturable process most probably glomerular filtration. Endogenous leptin is rapidly cleared from the circulation by glomerular filtration followed by metabolic degradation in the renal tubules.