In an attempt to identify and quantify the sites of atrial natriuretic peptide (ANP) degradation, a new tracer experiment has been developed. ¹²⁵I-ANP was injected as a bolus just upstream from the right atrium, and blood was sampled from two different sites (pulmonary artery and aorta) in eight cardiac patients. Data were analyzed using a physiologically based circulatory model consisting of three blocks in series (right heart, lungs and left heart, and periphery) supplied by the same flow (cardiac output, measured by thermodilution); the extraction coefficients of the three blocks and of the whole body could be determined from the areas under tracer concentration curves in plasma (AUCs). The values for AUCs (means ± SD) were 64.8 ± 9.4 and 65.5 ± 10.7% dose · l¹ · min¹ for pulmonary artery and aorta curves, respectively; the area under the pulmonary artery curve could be subdivided into the area under the first-pass curve (30.6 ± 4.7% dose · l¹ · min¹) and the area under the recirculating curve (34.0 ± 7.7% dose · l¹ · min¹). The metabolic clearance rate of ¹²⁵I-ANP, computed as dose divided by the area under the recirculating curve, was 3.1 ± 0.7 l/min, and the whole body extraction was 47.6 ± 6.6%. In our patients with myocardial dysfunction, neither right heart block nor lungs and left heart block significantly extracted ANP, and periphery block accounted for almost all removal of the hormone from the blood.