The present investigation was undertaken to define the hemodynamic determinants of lung uptake of thallium-201 (Tl-201) in man during stress. Graded tachycardia was induced by atrial pacing with continuous hemodynamic monitoring in 21 patients (6 normal, 15 with coronary artery disease). At peak pacing, 80 MEq (2.2 mCi) of Tl-201 was injected intravenously and imaging commenced within 5 minutes. Lung activity was expressed as a percentage of peak myocardial activity on the anterior image (Lung Tl-201 Index). The influence of rest, peak and post pacing hemodynamic parameters including cardiac index, pulmonary capillary wedge pressure, left ventricular end-diastolic pressure, pulmonary artery pressure, and heart rate on Lung Tl-201 Index was examined using step-wise multiple regression. Change in cardiac index from rest to peak pacing was negatively correlated, while pulmonary capillary wedge pressure at peak pacing was positively correlated to Lung Tl-201 Index (combined r value of 0.75). No other parameter had a significant correlation. In summary, lung uptake of Tl-201 activity during atrial pacing stress appears to depend on: (1) changes in cardiac output which may determine tissue contact time and thus influence extraction efficiency, and (2) hydrostatic pressure in the pulmonary capillary bed.