W e determined human and canine plasma clearance of atrial natriuretic factor (ANF) by lung, liver, and kidney from arteriovenous differences in plasma ANF and measured organ plasma flow. Human subjects had lower plasma ANF concentrations in the pulmonary vein or the pulmonary capillary wedge position when compared with the pulmonary artery, and both sites yielded pulmonary ANF extraction ratios of 24%. Canine lung ANF extraction was 19 +/- 3% and pulmonary ANF clearance was 328 +/- 78 ml/min per m2 vs. 357 +/- 53 ml/min per m2 in man. Hepatic plasma ANF clearance was 216 +/- 26 ml/min with an extraction ratio of 30 +/- 3% in humans and 199 +/- 89 ml/min and 36 +/- 6% in the dog. Renal plasma ANF clearance in human subjects was 78 +/- 12 ml/min per kidney and correlated well with each kidney's creatinine clearance (r = 0.58, P less than 0.05). The mean renal ANF extraction ratio was 35 +/- 4% in human subjects and 42 +/- 6% in the dog. These data quantitate the specific organ ANF clearances by lung, liver, and kidney in human subjects and in dogs and provide a rationale for elevated plasma ANF levels in cirrhosis, renal failure, and diseases accompanied by reduced perfusion of these organs. These findings support the conclusion that plasma ANF concentrations are dependent upon both the stimuli for ANF secretion as well as the specific organ clearances of ANF.