The plasma disappearance rate (metabolic clearance rate) of administered intact parathyroid hormone (intact PTH) was analyzed in awake dogs with indwelling hepatic and renal vein catheters. The metabolic clearance rate (MCR) of intact PTH was found to be very rapid, 21.6±3.1 ml/min per kg in 11 normal dogs. The liver accounted for the greatest fraction of the MCR of intact PTH (61±4%) by virtue of an arterial minus venous (a - v) difference across the liver of 45±3%. The renal uptake of intact PTH accounted for 31±3% of the MCR of intact PTH. The renal a - v difference for intact PTH of 29±2% was significantly greater than the filtration fraction indicating renal uptake of intact PTH at sites independent of glomerular filtration. Together, the hepatic and renal clearances of intact PTH accounted for all but a small fraction of the MCR of intact PTH. The MCR of intact PTH, rendered biologically inactive by oxidation, was markedly decreased to 8.8±1 ml/min per kg. The a - v difference of oxidized intact PTH was reduced both in the liver and kidney. These data suggested that the high uptake rates of intact PTH are dependent, at least in part, upon sites recognizing only biologically active PTH. Chronic renal failure (CRF) decreased the MCR of intact PTH to 11.3±1.3 ml/min per kg (n = 10). Both the hepatic and renal a - v differences of intact PTH were reduced in dogs with CRF. This resulted in reductions in the hepatic and renal clearance of intact PTH. These studies identify the liver as a major extrarenal site of PTH metabolism affected by CRF. They suggest that CRF impairs the function of the major uptake sites involved in intact PTH metabolism.