Endothelin (ET)-1, the potent vasoconstrictor and smooth muscle mitogen, is a likely mediator of human pulmonary arterial hypertension (PAH). High plasma levels and intrapulmonary synthesis of ET-1 are found in various types of PAH. ET-1 is normally cleared from the pulmonary circulation via ET-B receptors found on endothelial cells. It is not known how PAH, which reduces the amount of perfused vascular surface area in the lung, affects ET-1 clearance. It is also unknown how the amount of ET-B receptor expression, which may be altered in PAH, affects ET-1 clearance. We used an indicator dilution technique to measure the levels of first-pass pulmonary extract of trace quantities of 125I-ET-1 from circulating blood (mean [± SD] levels, 47 ± 7%). We then calculated the permeability surface product (normal range, 18 to 40 mL/s), an index of the functional vascular surface area that is available for ET-1 extraction. Patients with primary pulmonary hypertension (PPH) [n = 17] and PAH from connective tissue disease (CTD) [n = 12] were studied. For both groups, the mean ET extraction was slightly reduced (PPH patients, 39 ± 16%; CTD patients, 36 ± 16%), while the permeability surface product was reduced for most patients (PPH patients, 18 ± 10%; CTD patients, 19 ± 11%). However, 59% of patients had first-pass pulmonary extract levels within the normal range. Thus, in many patients with PAH, despite the reduced functional vascular surface area available for ET-1 clearance, high circulating ET-1 levels may relate more to excess production than to reduced clearance. The fact that ET-B receptor-mediated clearance is preserved in many patients may be of importance to the relative effectiveness of selective vs nonselective ET antagonists.