Using the isolated rat kidney perfused with an artificial medium containing glucose as the sole fuel, we studied the renal handling of immunoreactive arginine vasopressin (AVP) and determined the effect of various factors on the ability of the kidney to remove AVP. In control kidneys perfused with AVP at concentrations below 116 muU/ml, the organ clearance of AVP (OC(AVP)) was 1,145+/-47 (SE) mul/min, whereas glomerular filtration rate (GFR) averaged 515+/-37 mul/min. Filtration could thus account for up to 45% of the OC(AVP), the balance presumably being cleared from the peritubular circulation. Of the AVP filtered, only 38% could be recovered in the urine (urinary clearance AVP averaged 205+/-12 mul/min) suggesting that the balance was taken up by the tubular epithelium and degraded. Fractional excretion of filtered AVP rose significantly in the presence of anoxia and cold (10 degrees C) to 49 and 59%, respectively, but was not affected by ouabain or high levels of AVP (458+/-58 muU/ml). The OC(AVP) was not significantly altered by the absence of glucose in the perfusate, anoxia, or ureteral ligation, maneuvers that were associated with significant reductions in GFR. In these and the control experiments, there was a significant inverse correlation between GFR and peritubular clearance emphasizing the importance of the latter (r = -0.749; P < 0.001). Cold, ouabain, and high concentrations of AVP reduced the clearance of AVP by the kidneys. On the basis of these studies we conclude that the kidney clears AVP from the circulation via two pathways, glomerular clearance and peritubular clearance. This exposes both the luminal and contraluminal surfaces of the tubular cells to the hormone, allowing these cells to remove AVP from the filtrate and the peritubular compartment. Noteworthy is the observation that under several conditions when GFR falls reducing the glomerular clearance of AVP, peritubular clearance increases and the total clearance of AVP by the kidney remains constant.